The Use of the Voice Trainer App for Vocal Control in People with a Degenerative Ataxia: A Pilot Intervention Study.

Dysarthria is disabling in persons with degenerative ataxia. There is limited evidence for speech therapy interventions. In this pilot study, we used the Voice trainer app, which was originally developed for patients with Parkinson's disease, as a feedback tool for vocal control. We hypothesized that patients with ataxic dysarthria would benefit from the Voice trainer app to better control their loudness and pitch, resulting in a lower speaking rate and better intelligibility. This intervention study consisted of five therapy sessions of 30 min within 3 weeks using the principles of the Pitch Limiting Voice Treatment. Patients received real-time visual feedback on loudness and pitch during the exercises. Besides, they were encouraged to practice at home or to use the Voice trainer in daily life. We used observer-rated and patient-rated outcome measures. The primary outcome measure was intelligibility, as measured by the Dutch sentence intelligibility test. Twenty-one out of 25 included patients with degenerative ataxia completed the therapy. We found no statistically significant improvements in intelligibility (p = .56). However, after the intervention, patients were speaking slower (p = .03) and the pause durations were longer (p < .001). The patients were satisfied about using the app. At the group level, we found no evidence for an effect of the Voice trainer app on intelligibility in degenerative ataxia. Because of the heterogeneity of ataxic dysarthria, a more tailor-made rather than generic intervention seems warranted.

Neurofilament light chain: A novel blood biomarker in patients with ataxia telangiectasia.

AIM: Neurofilament light chain (NfL) is recognized as a blood biomarker in several neurodegenerative disorders, but its possible relevance in Ataxia Telangiectasia (A-T) has not been examined. The aim of this study was to investigate the biomarker potential of blood NfL concentrations in patients with A-T. METHOD: Blood (serum/plasma) NfL concentrations were measured in a Dutch and an American cohort of patients with A-T and compared to control values. Additionally, correlations between NfL concentrations and disease phenotype (classic versus variant A-T) were studied. RESULTS: In total 40 (23 Dutch and 17 American) patients with A-T (32 patients with classic A-T and 7 patients with variant A-T) and 17 age- and gender-matched (to the American cohort) healthy controls were included in this study. Blood (serum/plasma) NfL concentrations in patients with classic A-T and age ≤ 12 years were elevated compared to age matched controls. Patients with classic A-T > 12 years also had higher blood (serum/plasma) NfL concentrations (here: compared to age-dependent reference values found in the literature). Patients with classic A-T had higher blood (serum/plasma) NfL concentrations than patients with the variant phenotype. CONCLUSION: Blood (serum/plasma) NfL concentrations are elevated in patients with classic A-T and appear to correlate with the disease phenotype (classic versus variant). Therefore, blood (serum/plasma) NfL may be a promising biomarker in A-T.

Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases.

BACKGROUND AND PURPOSE: The diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries. METHODS: This is a multicentre, cross-sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country. RESULTS: Some EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients' accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries. CONCLUSIONS: The management of these conditions in EU countries is unequal. The survey provides evidence that a European care-focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted.

The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Excessive short-latency stretch reflexes in the calf muscles do not cause postural instability in patients with hereditary spastic paraplegia.

OBJECTIVE: To identify the role of hyperexcitable short-latency stretch reflexes (SLRs) on balance control in people with hereditary spastic paraplegia (PwHSP). METHODS: Sixteen PwHSP with triceps surae spasticity and 9 healthy control subjects were subjected to toes-up support-surface perturbations. EMG data were recorded from gastrocnemius, soleus and tibialis anterior. Furthermore, center-of-mass trajectories were recorded. RESULTS: PwHSP were less able to withstand the perturbations. Triceps surae SLRs (40-80 ms post perturbation) in PwHSP were increased compared to healthy subjects. Furthermore, a sustained triceps surae EMG activity at 220-320 ms post perturbation was observed in PwHSP, whereas control subjects demonstrated suppression of triceps surae activity. Center of mass trajectories started to diverge between PwHSP and controls only after ∼500 ms, with greater excursions being observed in the PwHSP. CONCLUSIONS: The present results confirm that balance control is impaired in PwHSP. However, the late instant of center of mass divergence argues against a direct, causative role of hyperexcitable SLRs in the triceps surae. SIGNIFICANCE: We postulate that enhanced short-latency stretch reflexes of the triceps surae do not underlie poor balance control in PwHSP. Instead, we suggest the lack of suppression of later triceps surae activity to be the main cause.

"Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.

BACKGROUND AND PURPOSE: The "ears of the lynx" MR imaging sign has been described in case reports of hereditary spastic paraplegia with a thin corpus callosum, mostly associated with mutations in the spatacsin vesicle trafficking associated gene, causing Spastic Paraplegia type 11 (SPG11). This sign corresponds to long T1 and T2 values in the forceps minor of the corpus callosum, which appears hyperintense on FLAIR and hypointense on T1-weighted images. Our purpose was to determine the sensitivity and specificity of the ears of the lynx MR imaging sign for genetic cases compared with common potential mimics. MATERIALS AND METHODS: Four independent raters, blinded to the diagnosis, determined whether the ears of the lynx sign was present in each of a set of 204 single anonymized FLAIR and T1-weighted MR images from 34 patients with causal mutations associated with SPG11 or Spastic Paraplegia type 15 (SPG15). 34 healthy controls, and 34 patients with multiple sclerosis. RESULTS: The interrater reliability for FLAIR images was substantial (Cohen κ, 0.66-0.77). For these images, the sensitivity of the ears of the lynx sign across raters ranged from 78.8 to 97.0 and the specificity ranged from 90.9 to 100. The accuracy of the sign, measured by area under the receiver operating characteristic curve, ranged from very good (87.1) to excellent (93.9). CONCLUSIONS: The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history.

[The yips: a movement disorder among golfers]. / De 'yips': een bewegingsstoornis bij golfers.

BACKGROUND: Although the yips occurs commonly in golfers, this neurological movement disorder is a relatively unknown phenomenon among physicians. CASE DESCRIPTION: A 47-year-old golf player developed a disturbing, neurological movement disorder that manifested when playing golf: the yips. These jerks occurred when putting, but not during practice rounds. The patient's father suffered from similar yips. CONCLUSION: The yips is a task-specific dystonia, which can also manifest in players of other sports. Multiple factors, such as genetic predisposition and anxiety seem to be involved in its pathophysiology. The disorder is relatively common among both professional and amateur golfers. The adverse impact can be big and a cure is yet to be found.

The wrong end of the telescope: neuromuscular mimics of movement disorders (and vice versa).

The rapid advances in modern neurology have led to increased specialisation in clinical practice. Being an expert in a neurology subspecialty offers advantages for diagnosing and managing specific disorders. However, specialisation also risks tunnel vision: interpreting symptoms and signs within one's own framework of reference, while ignoring differential diagnostic options from other subspecialties. This is particularly relevant when the patient's presentation potentially belongs to different neurological subspecialties. We illustrate this challenge by highlighting a series of clinical features that partially overlap between two common subspecialties: movement disorders and neuromuscular disorders. An overlap in clinical presentation is not rare, and includes, for example, involuntary eyelid closure (which could be active eye closure due to blepharospasm, or ptosis due to weakness). Other overlapping features include abnormal postures, involuntary movements and gait changes. We describe two of these overlapping features in more detail and emphasise the possible consequences of 'looking through the wrong end of the telescope' in such patients, as this may lead to a wrong differential diagnosis, unnecessary investigations and a delayed treatment start.

Drug-induced cerebellar ataxia: a systematic review.

BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMBASE (1988 to January 2014) to identify all of the drugs that can have ataxia as an ADR and to assess the frequency of drug-induced ataxia for individual drugs. Furthermore, we collected reports of drug-induced ataxia over the past 20 years in the Netherlands by querying a national register of ADRs. RESULTS: Drug-induced ataxia was reported in association with 93 individual drugs (57 from the literature, 36 from the Dutch registry). The most common groups were antiepileptic drugs, benzodiazepines, and antineoplastics. For some, the number needed to harm was below 10. Ataxia was commonly reversible, but persistent symptoms were described with lithium and certain antineoplastics. CONCLUSIONS: It is important to be aware of the possibility that ataxia might be drug-induced, and for some drugs the relative frequency of this particular ADR is high. In most patients, symptoms occur within days or weeks after the introduction of a new drug or an increase in dose. In general, ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs.

A gait paradigm reveals different patterns of abnormal cerebellar motor learning in primary focal dystonias.

Accumulating evidence points to a role of the cerebellum in the pathophysiology of primary dystonia. The aim of this study was to investigate whether the abnormalities of cerebellar motor learning in primary dystonia are solely detectable in more pure forms of cerebellum-dependent associative motor learning paradigms, or whether these are also present in other motor learning paradigms that rely heavily on the cerebellum but in addition require a more widespread sensorimotor network. Twenty-six patients with various forms of focal dystonia and 10 age-matched healthy controls participated in a motor learning paradigm on a split-belt treadmill. By using reflective markers, three-dimensional kinematics were recorded using a 6-camera motion analysis system. Adaptation walking parameters were analyzed offline, comparing the different dystonia groups and healthy controls. Patients with blepharospasm and writer's cramp were significantly impaired on various adaptation walking parameters. Whereas results of cervical dystonia patients did not differ from healthy controls in terms of adaptation walking parameters, differences in parameters of normal gait were found. We have here demonstrated abnormal sensorimotor adaptation with the split-belt paradigm in patients with blepharospasm and writer's cramp. This reinforces the current concept of cerebellar dysfunction in primary dystonia, and that this extends beyond more pure forms of cerebellum-dependent associative motor learning paradigms. However, the finding of normal adaptation in cervical dystonia patients indicates that the pattern of cerebellar dysfunction may be slightly different for the various forms of primary focal dystonia, suggesting that actual cerebellar pathology may not be a primary driving force in dystonia.

The clinical utility of botulinum toxin injections targeted at the motor endplate zone in cervical dystonia.

BACKGROUND AND PURPOSE: Cervical dystonia (CD) patients usually receive repeated botulinum neurotoxin (BoNT) injections. The aims of this study were to evaluate the feasibility of motor endplate zone (MEZ) detection of relevant cervical muscles in CD patients receiving chronic BoNT treatment and to compare the treatment effect of half-dosed, endplate-targeted injections to standard BoNT injections. METHODS: In study 1, high-density surface electromyography (HD-sEMG) was recorded from the sternocleidomastoid (SCM) and splenius capitis (SC) muscles in 18 CD patients with ongoing BoNT treatment, by which the location of the MEZ was determined. In study 2, nine additional patients with rotational-type CD participated in a treatment effect study where they received either half of their regular BoNT dose through endplate-targeted injections or their normal BoNT dose through standard injections (crossover design). Dystonia severity was recorded before and 4 weeks after each treatment session (Toronto Western Spasmodic Torticollis Rating Scale severity subscore). RESULTS: In the SCM muscle the MEZ was located at the lower border of the superior third part of the muscle, and in the SC muscle at half muscle length. Endplate-targeted, half-dosed BoNT injection resulted in a similar treatment effect to injecting the full dose in the standard technique. CONCLUSIONS: Half-dosed, endplate-targeted BoNT injections lead to a similar treatment effect to the standard BoNT injection protocol. MEZ detection confronts the clinician with some technical challenges, such as the ability of accurate and technically optimal placement of the electrode grid and correct interpretation of the HD-sEMG signal.

EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.

BACKGROUND AND OBJECTIVES: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. METHODS: This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force. DIAGNOSIS: If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases. TREATMENT: Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.

GLUT1 deficiency syndrome into adulthood: a follow-up study.

GLUT1 deficiency syndrome (GLUT1DS) is a treatable neurometabolic disorder in which glucose transport into the brain is disturbed. Besides the classic phenotype of intellectual disability, epilepsy, and movement disorders, other phenotypes are increasingly recognized. These include, for example, idiopathic generalized epilepsy and paroxysmal exercise-induced dyskinesia. Since the disorder has only been recognized for two decades and is mostly diagnosed in children, little is known about the disease course. Our purpose was to investigate the disease course of GLUT1DS patients with the classic, complex phenotype from infancy into adulthood. We performed a systematic literature review as well as a cohort study, including GLUT1DS patients aged 18 years and older. The literature search yielded a total of 91 adult GLUT1DS patients, of which 33 patients (one-third) had a complex phenotype. The cohort study included seven GLUT1DS patients with a complex phenotype who were prospectively followed up in our clinic from childhood into adulthood. Our results show that epilepsy is a prominent feature during childhood in classic GLUT1DS patients. During adolescence, however, epilepsy diminishes or even disappears, but new paroxysmal movement disorders, especially paroxysmal exercise-induced dyskinesia, either appear or worsen if already present in childhood. Intellectual disability was not systematically assessed, but cognitive functions appeared to be stabile throughout life. Like children, adolescents may benefit from a ketogenic diet or variants thereof.

Cerebellum-dependent associative learning deficits in primary dystonia are normalized by rTMS and practice.

Eyeblink classical conditioning (EBCC) is a cerebellum-dependent paradigm of associative motor learning, and abnormal EBCC is a neurophysiological indicator of cerebellar dysfunction. We have previously demonstrated impaired EBCC in patients with primary dystonia, but it remains uncertain if this represents actual cerebellar pathology or reflects a functional cerebellar disruption. We examined this further by: (1) studying acquisition and retention of EBCC in a second session in eight patients with cervical dystonia (CD) who had a first session 7-10 days earlier; and (2) by investigating the potential of continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere to modify a first-ever EBCC session in 11 patients with CD. EBCC data of eight healthy controls previously studied were used for additional between-group comparisons. We observed an improvement of EBCC in a second session in patients with CD, which is in contrast to patients with proven cerebellar pathology who do not show further improvement of EBCC in additional sessions. We also found that cerebellar cTBS paradoxically normalized EBCC in patients with CD, while we previously showed that it disrupts EBCC in healthy volunteers. Combined, these two experiments are in keeping with a functional and reversible disruption of the cerebellum in dystonia, a phenomenon that is probably secondary to either cerebellar compensation or to cerebellar recruitment in the abnormal sensorimotor network.

ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.

SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument.

Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.

Prospective analysis of falls in dominant ataxias.

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence.

Marinesco-Sjögren syndrome due to SIL1 mutations with a comment on the clinical phenotype.

BACKGROUND: Marinesco-Sjögren syndrome is an autosomal recessive cerebellar ataxia, characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to mutations in the SIL1 gene. METHODS: The clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjögren syndrome are described and compared to the literature on genetically proven Marinesco-Sjögren patients. RESULTS: The core phenotype of this syndrome appears homogeneous, but: [1] cataract can develop later than the motor and cognitive signs; [2] myopathy is an early feature that seems progressive during the course of the disease; [3] serum creatine kinase is normal or only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of intellectual disability is present in most Marinesco-Sjögren patients. CONCLUSIONS: Because the late appearance of some hallmarks and the uncertainty as to whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the diagnostic work-up of children with suspected inherited ataxias.

The cerebellum in dystonia - help or hindrance?

Dystonia has historically been considered a disorder of the basal ganglia. This review aims to critically examine the evidence for a role of the cerebellum in the pathophysiology of dystonia. We compare and attempt to link the information available from both clinical and experimental studies; work detailing cerebellar connectivity in primates; data that suggests a role for the cerebellum in the genesis of dystonia in murine models; clinical observation in humans with structural lesions and heredodegenerative disorders of the cerebellum; and imaging studies of patients with dystonia. The typical electrophysiological findings in dystonia are the converse to those found in cerebellar lesions. However, certain subtypes of dystonia mirror cerebellar patterns of increased cortical inhibition. Furthermore, altered cerebellar function can be demonstrated in adult onset focal dystonia with impaired cerebellar inhibition of motor cortex and abnormal eyeblink classical conditioning. We propose that abnormal, likely compensatory activity of the cerebellum is an important factor within pathophysiological models of dystonia. Work in this exciting area has only just begun but it is likely that the cerebellum will have a key place within future models of dystonia.

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

OBJECTIVE: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. METHODS: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. RESULTS: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. CONCLUSIONS: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.