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Background: Tics are the hallmark of Tourette syndrome (TS) and chronic tic disorders (CTD). Although typically involving the face, especially at onset, tics may involve any muscle under voluntary control, including axial muscles of the neck (causing head movements), shoulders and trunk (thorax and abdomen). We aimed to characterize these tics and provide a clinical frame for their associations and complications., Materials and Methods: We reviewed video recordings and clinical history of 196 patients with TS or CTD according to DSM-5., Results: Any axial tic was identified in 75% of patients. Tic distribution were head (n = 113, 57.6%), shoulder (n = 91, 46.4%), and trunk (n = 63, 32.2%). There were no differences in sex, age at onset or at evaluation between patients with and without axial tics. The most common axial tics by anatomical distribution were head turning, bilateral synchronous shoulder elevation and trunk jerks; however, tic phenomenology was quite variable. A greater severity of tics (P = 0.018) was associated with axial tics in the multivariate regression analysis. Head/neck tics associated with simple phonic tics (P = 0.002); whereas shoulder and trunk tics associated with complex motor tics (P < 0.05) in a bivariate analysis. Neck pain, breathing interference, sleep limitation and radiculopathy, secondary to axial tics were complications observed in a proportion of these cases., Conclusions: Axial tics are commonly observed in patients with TS/CTD with variable phenomenology. They associate with greater tic severity, phonic tics and complex motor tics. They may result in neck pain, breathing interference, sleeping problems and cervical spine injuries., Competing Interests: Declarations Conflicts of interest On behalf of all the authors, the corresponding author states that there is no conflict of interest., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Leg stereotypy syndrome (LSS) is a very common, yet underrecognized condition. The pathophysiology of the condition is not well understood., Objective: To evaluate and describe the visual kinematic characteristics of the repetitive leg movements in individuals with LSS., Methods: In this study, we identified and videotaped individuals diagnosed with LSS at the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas between 2000 and 2023. Only patients with LSS and without any co-morbidities were included in the study. Their medical records were carefully reviewed, and the demographic and clinical data were entered into a database. Video recordings of the repetitive leg movements were then analyzed using TremAn software., Results: We identified 14 individuals with LSS who were videotaped at our center. The videos of the 5 cases were too brief and therefore not suitable for TremAn quantitative analysis. The remaining 9 individuals exhibited regular rhythmic oscillations of the legs. Among these, two individuals displayed rhythmic movements only in video segments where their legs were in crossed positions. The other 7 individuals had regular rhythmic oscillations, always with the toes resting on the floor with the heels raised. Frequency analysis showed values between 4.5 and 6.5 Hz, fairly consistent with a variance below 0.5 Hz in individual cases. The oscillation frequency changed from 5.7 Hz to 2.7 Hz while standing., Conclusion: In this study, 6 of 9 individuals with LSS showed 4.5-6.5 Hz regular rhythmic leg movements. Studies involving a larger LSS population with additional electrophysiological evaluations are needed to obtain further insights into this common movement disorder., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia., Methods: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year., Results: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT., Conclusion: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia., (© 2023. The Author(s).)

Objectives: We aimed to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine for treatment of Tourette syndrome, focusing on therapeutic benefits, side effect profile, and accessibility for the off-label use of these drugs., Methods: We performed a retrospective chart review, supplemented with a telephone survey, of all our patients treated for their tics with VMAT2 inhibitors over a period of 4 years from January 2017 until January 2021., Results: We identified 164 patients treated with the various VMAT2 inhibitors (tetrabenazine, n = 135; deutetrabenazine, n = 71; valbenazine, n = 20). Data on the mean treatment duration and daily dosages were collected. The response to VMAT2 inhibitors was assessed by a Likert scale by comparing the symptom severity before initiation and while on treatment. Side effects were mild and mostly consisted of depression as the major side effect but there was no suicidality reported., Conclusion: VMAT2 inhibitors are effective and safe in the treatment of tics associated with Tourette syndrome but are not readily accessible by patients in the United States, partly because of lack of approval by the Food and Drug Administration., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Tics are rapid, recurrent, non-rhythmic movements or emitted sounds. Tics are the hallmark of Tourette syndrome (TS); however, a number of other disorders may be associated with tics, so-called secondary tic disorders (STD). We assessed clinical history and performed blinded evaluations of video-recordings from patients with TS and STD in order to identify features that may differentiate tics associated with TS vs STD. There were 156 patients with TS and 38 with STD, 21 of whom had functional (psychogenic) tics. Patients with TS were more frequently male and had a younger age at onset. Tics in TS tend to involve muscles in the cranial-cervical area more often and have greater severity and complexity than those in patients with STD. Similar findings were observed when contrasting patients with TS with patients with functional tics only. Simple phonic tics showed the greatest diagnostic accuracy for TS, compared with STD, but marked overlap in the types of tics and comorbidities was observed between patients with TS and STD. Patients with TS were more likely males, had a younger age at onset, phonic tics and motor tics affecting predominantly the head and neck area, and had a greater complexity and severity of tics than those with STD. When these features are absent a consideration should be given to the possibility of a tic disorder other than TS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited., Methods: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed., Results: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence., Conclusions: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn., (© 2023. The Author(s).)

Background: Tourette syndrome (TS) is the most common cause of chronic tics. Patients with TS frequently manifest motor tics involving the eyes and face but oromandibular (OM) tics have been rarely studied., Materials and Methods: We reviewed the medical records and video-recordings of 155 consecutive patients with TS in our movement disorders clinic. In addition, we studied 35 patients with classic tardive dyskinesia (TD) and compared their clinical and demographic features with those with TS., Results: We identified 41 patients with OM tics (26.5%). Although patients with OM tics had a greater overall tic severity and higher frequency of.complex motor and phonic tics, in the bivariate analysis, only comorbid dystonic tics (P = 0.001), greater number of affected body parts (P = 0.012) and more frequent eye-rolling tics (P = 0.059) were included in the final regression model after controlling for other variables. When compared with patients with OM tics, patients with classic TD had more frequently masticatory movements (sensitivity, 0.86; specificity, 0.95), continuous tongue movements (sensitivity, 0.71; specificity, 1.0) and continuous OM movements (sensitivity, 0.4; specificity, 1.0)., Conclusions: OM tics are common and often troublesome or even disabling symptoms in patients with TS. They may be difficult to differentiate from TD, but the latter is typically manifested by continuous orolingual and masticatory movements., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Dystonic tics differ from clonic tics by their slower and more sustained nature. Dystonic tics are often present in patients with Tourette syndrome (TS) and other tic-disorders. However, their phenomenology and impact on overall impairment have not been extensively studied., Materials and Methods: We assessed clinical history and tic duration in video-recordings from patients with TS evaluated at our movement disorders clinic. Dystonic tics were defined as those lasting ≥ 1000 ms (ms)., Results: Of the total of 201 patients with TS, there were 156 with video-recordings suitable for tic duration analysis, of their tics, 57 (36.5%) of whom had dystonic motor tics, including 9 (5.7%) with dystonic phonic tics. Dystonic motor tics had a duration range between 1033 and 15,000 ms and dystonic phonic tics between 1132 and 17,766 ms. Patients with dystonic tics were older 24.4 vs. 16.5 years (P = 0.005) and had an older age at onset 12.9 vs. 7.2 years (P < 0.001), than patients without dystonic tics. The bivariate analysis showed an association between the presence of dystonic tics, greater tic severity and wider body distribution. The multivariate regression analysis showed a statistical association with older age at evaluation (P = 0.001), greater tic severity on video-recordings (P = 0.001) and co-occurrence with complex motor tics (P = 0.020). The presence of dystonic tics increased the risk for being considered for deep brain stimulation therapy, odds ratio: 15.7 (P = 0.002)., Conclusion: Dystonic tics, observed in about a third of patients with TS, are associated with increased severity of TS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Tourette syndrome (TS) is characterized by the presence of motor and phonic tics, as well as a variety of behavioral co-morbidities. Self-injurious behavior (SIB) is one of the most serious manifestations of TS, but its pathophysiology is poorly understood., Methods: Consecutive patients with TS studied in a tertiary care center., Results: We identified a total of 34 patients (16.9%) with SIB from a cohort of 201 patients with TS. Most of these patients (n = 23, 11.4%) experienced self-directed damage; while others had outward-directed (n = 7, 3.5%) or tic-related SIB (n = 4, 2%). Compared to other patients with TS, those who manifested SIB (self- and outward-directed damage) were more likely to have tics involving shoulder (P = 0.046), trunk (P = 0.006), and arm (P = 0.017); as well as dystonic tics (P = 0.016); complex motor tics (P < 0.001), copropraxia (P = 0.045), complex phonic tics (P = 0.003), higher number of phonic tics (P = 0.001), verbalizations (P = 0.001), coprolalia (P = 0.006) and obsessive compulsive disorder (OCD) (P < 0.001) as determined by bivariate analysis. In the multivariate analysis only complex motor tics (P = 0.006), obsessive-compulsive behavior (P = 0.025) and greater severity of tics (P = 0.002) showed a statistically significant association with SIB. Patients with SIB had a greater probability of being selected for deep brain stimulation (DBS) therapy by the treating clinician (P = 0.01)., Conclusions: SIB is observed in about 17% of patients with TS. The presence of complex motor tics, OCD and greater severity of tics was related to the presence of SIB., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Tics are the hallmark of Tourette syndrome (TS). However, TS patients may have a particular vulnerability to develop other movement disorders (MDs), such as dystonia, chorea, stereotypy, and other hyperkinetic disorders that may be wrongly attributed to tics., Materials and Methods: We studied a cohort of 201 patients with motor and phonic tics associated with TS to determine if they have additional, co-existent, MDs., Results: There were 67 (33.3%) patients with comorbid non-tic MDs. Phenomenology-wise, piano-playing movements resembling chorea or myoclonus, were the most common non-tic movement, observed in 11% of cases, followed by stereotypies (8.0%), tremor, dystonia and parkinsonism, 5.0% each. Drug-induced was the most common etiology (6.0%), followed by functional movement disorders (5.0%) and tardive phenomena (5.0%). No clear etiology was identified in most patients. Piano-playing movements, were associated with a younger age at onset (P = 0.004) and younger age at presentation (P < 0.001). Patients with drug-induced movements and tardive phenomena had a lower frequency of craniofacial tics. FMDs, and idiopathic MDS showed no specific associations with TS. Tic severity was not a predictor of any co-existent MD., Conclusion: About a third of patients with TS present with comorbid MDs which should be differentiated and distinguished from tics as their etiopathogenesis and treatment may be different., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Although head tremor (HT) and pain are prevalent in cervical dystonia (CD), their joint relationship to phenotypic features of focal dystonia remains unclear., Objectives: We examined how severity of HT and pain are associated with age of CD onset and duration, and whether HT subtypes ("jerky" or "regular") exhibit distinct relationships between severity of HT and pain., Methods: The severity of HT and pain were assessed with the Toronto Western Spasmodic Torticollis Rating Scale in retrospective review of 188 CD patients recruited through the Dystonia Coalition., Results: HT severity was associated with longer CD duration (p < 0.0005), whereas pain severity was associated with younger age at onset (p = 0.043). HT severity and pain severity were not correlated for jerky HT (p = 0.996), but positively correlated for regular HT (p = 0.01)., Conclusions: The distinct associations of HT and pain with age at onset, disease duration, and HT subtype further characterize the heterogeneity of CD's clinical presentation and suggest similarly heterogeneous underlying mechanisms.

Motor and phonic tics associated with Tourette syndrome (TS) can range in severity from barely perceptible to disabling and most patients have a variety of behavioral co-morbidities, particularly, attention deficit disorder and obsessive compulsive disorder. Therefore, therapy must be tailored to the individual needs of the patients. In addition to behavioral therapy, oral medications such as alpha agonists, dopamine depletors, anti-psychotics, and topiramate are used to control the involuntary movements and noises. Botulinum toxin injections are particularly effective in patients with troublesome focal motor and phonic tics, including coprolalia. Deep brain stimulation may be considered for patients with "malignant" TS, that is, refractory to medical therapy. When appropriate therapy is selected and implemented, most patients with TS can achieve their full potential and lead essentially normal life.

Background: Cervical dystonia (CD) can present with head tremor. It is unclear whether ataxic features are differentially associated with this phenotype at onset of CD., Objectives: We sought to evaluate: (1) the demographic features of CD patients with (Tr-CD) and without head tremor (nTr-CD) at onset, and (2) the differential ataxic features between these CD subtypes., Methods: For the first objective, we compared demographic data in Tr-CD versus nTr-CD subtypes in the entire cohort of CD subjects enrolled in the Dystonia Coalition Natural History and Biorepository studies (n = 1608). For the second objective, we rated the standardized videos from consecutively enrolled Tr-CD subjects (n = 50) and age-, gender-, and disease duration-matched nTr-CD subjects (n = 50) for ataxia severity scoring using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS); and for dystonia severity using the Toronto Western Spasmodic Torticollis Rating Scale section-I (TWSTRS) and the Global Dystonia Rating Scale (GDRS)., Results: Of 1,608 subjects, 18.1% (n = 291) were classified as Tr-CD and 81.9% (n = 1317) as nTr-CD. The Tr-CD cohort was older, predominantly female, and had longer disease duration than the nTr-CD cohort (p = 0.01). Compared to nTr-CD, Tr-CD subjects had worse generalized ataxia, speech, and gait and posture scores. High ataxia severity with low dystonia severity distinguished Tr-CD from nTr-CD with high accuracy (area under the curve, 0.91 (95% CI 0.85-0.97)., Conclusions: Head tremor at disease onset represents a clinically distinguishable subtype of cervical dystonia affecting predominantly older women, with worse ataxia and milder dystonia than the non-tremulous dystonic phenotype.

Hand and foot deformities, known as "striatal deformities", and other musculoskeletal abnormalities such as dropped head, bent spine, camptocormia, scoliosis and Pisa syndrome, are poorly understood and often misdiagnosed features of Parkinson's disease and other parkinsonian syndromes. These deformities share some similarities with known rheumatologic conditions and can be wrongly diagnosed as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, Dupuytren's contracture, trigger finger, or other rheumatologic or orthopedic conditions. Neurologists, rheumatologists, and other physicians must be familiar with these deformities to prevent misdiagnosis and unnecessary diagnostic tests, and to recommend appropriate treatment options.

Objective: To investigate the prevalence of substance abuse (SA) in patients with cervical dystonia (CD) and to correlate it with prevalence of psychiatric disorders., Methods: Data on anxiety, depression, dystonia severity, and substance abuse were collected from ten sites participating in the Dystonia Coalition. Patients were divided into two groups according to the presence of SA, utilizing Structured Clinical Interview for DSM-4 criteria. Wilcoxon Rank-Sum test was used to analyze the difference in median scores on the questionnaires between the groups. Chi-square test was used to analyze association between opiate and benzodiazepine use and SA. Association between TWSTRS severity and SA and medication use was assessed. A two-tailed p value of < 0.05 was considered significant. SAS 9.3 (SAS Institute Inc., Cary, NC, USA) was used for all analyses., Results: Of 208 CD patients, 23 (11%) were identified with SA; 26.3% of patients with SA were on opiates compared to 7.2% of CD patients without SA (p = 0.006). Compared to non-SA patients, those experiencing SA were more likely male (88.9%; p = 0.0007), younger (median age 55; p = 0.031), and scored worse on questionnaires assessing depression (p = 0.044, p = 0.005), anxiety (p = 0.003), and dystonia psychiatric severity (p = 0.033). The median TWSTRS motor severity scores were higher in SA patients compared to non-SA patients (20 versus 16, p = 0.0339). The median TWSTRS total disability, motor, and pain scores were higher in patients on opiates than patients who were not (12 versus 8, p = 0.0071; 18.5 versus 16, p = 0.0243; 12.4 versus 6.7, p = 0.0052, respectively)., Conclusions: Potential risk factors for SA in CD patients include younger age and male gender with comorbid anxiety, depression and other psychiatric problems. Caution should be exercised when prescribing drugs with potential for abuse in these patients.

Functional (psychogenic) movement disorders (FMDs) may present with a broad spectrum of phenomenology including stereotypic movements. We aimed to characterize the phenomenology of functional stereotypies and compare these features with those observed in 65 patients with tardive dyskinesia (TD). From a cohort of 184 patients with FMDs, we identified 19 (10.3%) with functional stereotypies (FS). There were 15 women and 4 men, with a mean age at onset of 38.6 ± 17.4 years. Among the patients with FS, there were 9 (47%) with orolingual dyskinesia/stereotypy, 9 (47%) with limb stereotypies, 6 (32%) with trunk stereotypies, and 2 (11%) with respiratory dyskinesia as part of orofacial-laryngeal-trunk stereotypy. These patients showed signs commonly seen in FMDs such as sudden onset (84%), prominent distractibility (58%), and periods of unexplained improvement (84%) that were not reported in patients with TD. Besides a much lower frequency of exposure to potential offending drugs, patients with FS differed from those with classic TD by a younger age at onset, lack of self-biting, uncommon chewing movements, more frequent lingual movements without mouth dyskinesia, and associated functional tremor and abnormal speech. Lack of self-biting showed the highest sensitivity (1.0) and abnormal speech showed the highest specificity (0.9) for the diagnosis of functional orolingual dyskinesia. FS represent part of the clinical spectrum of FMDs. Clinical and demographic features are helpful in distinguishing patients with FS from those with TD.

Hemifacial spasm (HFS) is one of the most common presentations in patients with cranial psychogenic (functional) movement disorders (PMD). Medical records and videos of patients with PMD and HFS were reviewed to identify those with psychogenic HFS and to compare the phenomenology of psychogenic HFS with organic HFS. We identified 18 (9.8%) patients with psychogenic HFS from a cohort of 184 patients with PMDs. There were 14 (78%) women and 4 men, with a mean age at onset of 33 ± 13.5 years. These were compared with 37 consecutive patients with organic (primary) HFS. Patients with psychogenic HFS were significantly younger and had more frequently tonic muscle contractions, bilateral asynchronous hemifacial involvement, isolated lower facial involvement, downward deviation of the mouth's angle, and lack of the "other Babinski sign" compared to those with organic HFS. Other features such as ipsilateral downward movements of the eyebrow; associated tremor, dystonia and hemi-masticatory spasms were more frequently observed in patients with psychogenic HFS but these differences did not reach statistical significance. Lack of other Babinski sign and tonic muscle contractions showed the highest sensitivity (1.00 and 0.87, respectively), whereas downward mouth's angle deviation showed the highest specificity (1.00) for the diagnosis of psychogenic HFS. Besides other features such as suggestibility, distractibility, periods of unexplained improvements observed in most patients with PMDs, several clinical features, such as tonic muscle contractions, downward mouth's angle deviation, predominant lower facial and bilateral involvement, may be helpful in distinguishing psychogenic from organic HFS.

Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders.

Psychogenic speech and voice disorders (PSVDs) may occur in isolation but more typically are encountered in the setting of other psychogenic disorders. We aimed to characterize the phenomenology, frequency, and correlates of PSVDs in a cohort of patients with psychogenic movement disorders (PMDs). We studied 182 consecutive patients with PMDs, 30 of whom (16.5 %) also exhibited PSVD. Stuttering was the most common speech abnormality (n = 16, 53.3 %), followed by speech arrests (n = 4, 13.3 %), foreign accent syndrome (n = 2, 6.6 %), hypophonia (n = 2, 6.6 %), and dysphonia (n = 2, 6.6 %). Four patients (13.2 %) had more complex presentations with different combinations of these patterns. No differences in gender, age at onset, and distribution of PMDs were observed between patients with and without PSVD. PSVDs are relatively frequent in patients with PMDs and are manifested by a wide variety of abnormal speech and voice phenomena, with stuttering being the most common presentation. Speech therapy and insight-oriented counseling may be helpful to some patients.

Mild parkinsonian features can be observed in patients with essential tremor (ET). Although dopamine transporter (DAT) imaging is usually normal in ET, some studies found mild dopaminergic deficit in ET patients compared to healthy controls (HC). We analyzed clinical and DAT imaging data in ET patients with and without parkinsonian features. Thirty-nine ET patients with and without parkinsonian features and 13 HC underwent detailed examination by a movement disorders neurologist and 123-I ioflupane SPECT. Two independent radiologists "blinded" to the clinical diagnosis analyzed images visually and by semi-quantitative calculation of striatal binding ratios in different volumes of interests. ET patients were divided into pure ET group (no parkinsonian features, n = 22), ET-P [one parkinsonian feature not sufficient for the clinical diagnosis of Parkinson's disease (PD), n = 9], and ET + PD (two or more parkinsonian features meeting diagnostic criteria for PD, n = 8). As expected, ET + PD patients had the lowest striatal binding ratios. We also found a trend toward slightly lower striatal binding ratios in ET patients ET compared to HC, especially in caudate nucleus. There was no significant correlation between striatal binding ratios, ET severity or duration. Patients with ET and parkinsonian features represent a heterogeneous group that includes ET + PD and ET-P. The latter group shares some clinical features with PD but has no dopaminergic deficit on DAT imaging as determined by visual image interpretation. On the other hand, minimal dopaminergic deficit (as compared to controls) is detected in some ET patients with semi-quantitative image analysis, although the pattern may be different from that of PD.

To compare profiles of subjects with and without cervical dystonia (CD)-associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0-3] and moderate/severe pain groups (PNRS score 4-10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 ± 5.1 vs. 16.2 ± 5.6, p < 0.0001) and Disability (12.7 ± 6.1 vs. 7.5 ± 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 ± 82.9 vs. 158.0 ± 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 ± 1.4 vs. 3.7 ± 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition.

Movement disorders (MDs), particularly chorea, may be the presenting neurological complication of systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS), but the association is not often initially recognized. Current evidence suggests an autoimmune mechanism related to antiphospholipid antibodies in these two conditions, although the antigenic target within the central nervous system has not yet been identified. Based on a comprehensive review of the literature, this article summarizes the current knowledge on MDs in SLE and APS. A high index of suspicion is required to make an early diagnosis and initiate appropriate treatment to provide symptomatic relief and to prevent other systemic complications related to the autoimmune process.

IncobotulinumtoxinA (Xeomin(®), NT 201) is a purified botulinum toxin type A free from accessory (complexing) proteins. Previous studies evaluated single sets of incobotulinumtoxinA injections for the treatment of blepharospasm. Individualized injection intervals and other potential determinants of efficacy and safety need to be evaluated in a prospective, longitudinal study. Subjects with blepharospasm who completed a ≤ 20 weeks double-blind, placebo-controlled main period entered a ≤ 69 weeks open-label extension period (OLEX) and received ≤ 5 additional incobotulinumtoxinA treatments at flexible doses (≤ 50 U per eye) and flexible injection intervals (minimum of 6 weeks). Outcome measures included Jankovic Rating Scale (JRS) (sumscore, severity subscore and frequency subscore), Blepharospasm Disability Index, and adverse events. All 102 subjects who completed the main period entered the OLEX; 82 subjects completed the study, 56 received the maximum five injections. From each injection visit to a control visit 6 weeks later, investigator-rated JRS sumscores and subscores, and patient-rated Blepharospasm Disability Index were significantly improved (p ≤ 0.001 for all). All scores were still significantly improved at trial termination compared with the first injection visit (p < 0.05 for all). The most frequently reported adverse events were eyelid ptosis (31.4 %) and dry eye symptoms (17.6 %). The injection interval had no impact on the incidence of adverse events (post hoc analysis). No subject developed neutralizing antibodies during the study. Repeated incobotulinumtoxinA injections, administered at flexible doses and injection intervals from 6 to 20 weeks according to subjects' needs, provide sustained efficacy in the treatment of blepharospasm with no new or unexpected safety risks.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of dopamine (DA) neurons in the substantia nigra (SN). Currently, there are numerous therapeutic drugs for the treatment of PD; however, they are limited in efficacy and primarily target motor symptoms. Furthermore, these drugs have various adverse effects after long-term use. Usually, PD patients begin to take anti-parkinsonian drugs when they have developed obvious motor symptoms. At that time, a significant portion of the DA neurons in SN has been lost and the biology of the disease may have already been present for over a decade. This stage of PD diagnosis underscores the need for biomarkers that accurately indicate the onset of PD in order to apply disease-modifying therapies at an earlier stage of disease. However, development of disease modifying drugs has faced many setbacks, mostly due to the ways in which clinical trials are planned and executed. In this review paper, we summarize the recent findings of genetic biomarkers such as SNCA, LRRK2, parkin, PINK1, DJ1, etc., as well as evaluate the imaging techniques such as single proton emission computed tomography and positron emission tomography for their potential in diagnosing PD at earlier stages. Clinical trial designs, along with a comprehensive analysis of neuroprotective drugs for future treatment of PD, are also reviewed.

Iron is an essential element for multiple functions of the brain. Maintenance of iron homeostasis involves regulation of iron influx, iron efflux and iron storage. Mismanagement of brain iron has been implicated in neuronal injury and death in several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (PD) and Amyotrophic lateral sclerosis (ALS). Multiple iron chelators have been shown neuroprotective and neurorestorative in these diseases, suggesting that iron chelation might be a promising therapeutics. In this paper, we briefly review the new findings of biological function of several molecules that regulate iron homeostasis in the brain, the possible role of iron mismanagement in the pathogenesis of PD, AD and ALS, and then discuss the putative mechanisms for current available iron chelators as potential therapeutics for neurodegenerative diseases.

Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n= 633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR) =0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020-1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.

Cirrhosis and its co-morbidities may cause a variety of neurological complications, the most common being bouts of toxic metabolic encephalopathy. A proportion of patients with chronic liver disease develop acquired hepatocerebral degeneration (AHD), a chronic progressive neurological syndrome characterized by parkinsonism, ataxia and other movement disorders. This article reviews the clinical spectrum, pathophysiology, neuroimaging features and differential diagnosis of AHD along with emerging treatment options.

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.

The objective of this study was to analyze a sample of unrelated individuals with autosomal dominant essential tremor (ET) for a genetic association with loci in a candidate region (ETM2) on chromosome 2p24.1 that harbors a disease gene for ET. ET is a common movement disorder that is genetically linked to ETM2 in four large families. It is unknown whether this candidate locus is associated with dominantly inherited ET in other individuals. Based on information from previous genetic linkage studies, a linkage disequilibrium study was designed to compare individuals with a family history of ET (n=45) with normal controls (n=70). Three unreported dinucleotide polymorphic loci (etm1240, etm1231, and etm1234) were identified on a physical map of the ETM2 interval in a region of no recombination. The study sample was tested for allele frequency differences by the CLUMP program and haplotypes were analyzed by the FASTEHPLUS program. The allele frequencies were significantly different between ET cases and the control samples for the loci etm1231 (P< or =0.0419) and etm1234 (P<0.0001). A haplotype formed by the loci etm1231 and etm1234 occurred with a frequency of 29% in cases (n=45) and 9% in a white newborn sample (P<0.0001, n=35). The haplotype was not found in normal individuals older than 60 years without tremor (P=0.0063, n=35). This study provides evidence that an ancestral haplotype on chromosome 2p24.1 segregates with the ET disease phenotype in individuals with a family history of the disorder and will facilitate the search for a causative gene.

Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323&#95;Tyr328del) in the TOR1A gene was found in a patient with early onset dystonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.

Progressive supranuclear palsy (PSP) and cortocobasal degeneration (CBD) are often clinically confused with each other because they share a rapid disease progression, parkinsonism that responds poorly or transiently to levodopa therapy, and associated signs (e.g., ocular abnormalities, pyramidal signs and cognitive involvement). To improve the accuracy in diagnosing these disorders, this study examined the clinical features of 51 patients pathologically diagnosed with PSP and CBD. Logistic regression analysis identified two sets of predictors (models) for CBD patients, one consisting of asymmetric parkinsonism, cognitive disturbances at onset and instability and falls at first clinic visit, and the other one of asymmetric parkinsonism, cognitive disturbances at symptom onset and speech disturbances. While PSP patients often had severe postural instability at onset, symmetric parkinsonism, vertical supranuclear gaze palsy, speech and frontal lobe-type features, CBD patients presented with lateralized motor (e.g., parkinsonism, dystonia or myoclonus) and cognitive signs (e.g., ideomotor apraxia, aphasia or alien limb). On the other hand, CBD patients presenting with an alternate phenotype characterized by early severe frontal dementia and bilateral parkinsonism were generally misdiagnosed. PSP patients without vertical supranuclear gaze palsy were misdiagnosed. Recognizing the features which differentiate these disorders and the less obvious disease presentations as well as developing an increased index of suspicion will improve the diagnostic accuracy of these disorders.

Background: Progressive supranuclear palsy (PSP) is a neurologic syndrome of unknown cause. This idiopathic type of PSP is usually associated with characteristic clinical and pathological features., Objective: To assess evidence of cerebrovascular disease in a population of patients with clinically defined PSP, and to compare clinical and neuroimaging features in vascular versus idiopathic PSP., Design and Methods: Using predetermined criteria, the records of 128 patients diagnosed with PSP were reviewed for evidence of vascular disease., Results: Thirty patients (23.3%) satisfied criteria for vascular PSP. The vascular group differed from the idiopathic group by asymmetric and predominantly lower body involvement (p < 0.05). Corticospinal signs, pseudobulbar signs, gait difficulties, dementia, and incontinence of bowels and bladder were also more common in the vascular group, but these differences did not reach statistical significance., Conclusion: PSP is a syndrome which can be caused by cerebro-vascular disease. In addition to an increased frequency of stroke risk factors and neuroimaging evidence of vascular disease, vascular PSP can be differentiated from idiopathic PSP by a higher degree of asymmetry, lower body involvement, and evidence of corticospinal and pseudobulbar signs.