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Introduction: Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease. Methods: Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software. Results: There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer. Conclusions: The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency. [ABSTRACT FROM AUTHOR]

Background A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD. Methods Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations. Results For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [123I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD. Conclusions The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease. [ABSTRACT FROM AUTHOR]

To determine the prevalence of acquired hepatocerebral degeneration (AHD), its clinical and neuroimaging characteristics and response to treatments. Acquired hepatocerebral degeneration is a chronic encephalopathy with predominant motor signs in the context of severe liver disease. Its clinical picture is not well defined, and its prevalence and risk factors are not well known. Review of a database of 1000 patients with cirrhosis to identify cases of AHD. Clinical and neuroimaging data, follow-up and response to treatments, including liver transplantation, were recorded. Eight patients with AHD were identified. Its prevalence was 0.8% of patients with cirrhosis. The main risk factor for AHD was the presence of portosystemic shunts. Movement disorders, especially a combination of parkinsonism and cerebellar signs were observed in all patients. All AHD cases showed on MRI T1-weighted images hyperintensities in the globus pallidus, and 75% had extrapallidal involvement as well. Antiparkisonian drugs and treatments to prevent acute encephalopathies were ineffective. Three patients who underwent liver transplantation did not experience neurological improvement. Persistence of portosystemic shunts was demonstrated in two cases. Acquired hepatocerebral degeneration is a chronic encephalopathy which occurs in ∼1% of patients with liver cirrhosis and seems related to portosystemic shunts. Its is characterized by a combination of parkinsonism and cerebellar signs. MRI pallidal and extrapallidal lesions are seen in most patients, probably reflecting intracerebral deposits of manganese. Liver transplant did not improve the neurological signs in our patients, perhaps because of the persistence of portosystemic shunts. [ABSTRACT FROM AUTHOR]

Background: Dystonia is a complex clinical syndrome originated by a wide range of aetiologies. The diagnosis of dystonia is made after the evaluation of aetiological, phenomenological and genetic factors. Medications, except in patients with dopa-responsive dystonia, are of limited efficacy. Botulinum toxin injections are not applicable to patients with generalised dystonia, since many muscular groups contribute to disability. Clinical studies in children and adults with primary generalised dystonia (PGD) have reported beneficial effects of bilateral GPi deep brain stimulation (DBS) in both motor symptoms and disability produced by dystonia as well as a favourable impact of DBS in the health-related quality of life (HRQoL). Some clinical aspects of GPi stimulation in primary dystonia still remain controversial such as the influence of disease duration or age at onset in determining the postoperative clinical outcome.Results: The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia. [ABSTRACT FROM AUTHOR]

A literature review was conducted to assess risk of cardiac valve regurgitation (CVR) associated with use of ergot-derived and non-ergot dopamine agonists (DAs) in patients with Parkinson’s disease (PD). Inclusion criteria: case-control/observational studies of >10 patients with PD treated with DAs, including a control group and assessment of incidence/risk of CVR. Of the 166 publications identified, 14 met all inclusion criteria and included 1,750 patients. In 11 of the studies, a significant increase in CVR frequency of any severity (at the aortic, mitral or tricuspid valve) in the ergot group vs. the non-ergot or control group was described. No study reported increased risk of CVR for non-ergot DAs, compared with controls. In the studies identified in the literature, the use of ergot-derived DAs (pergolide and cabergoline) in patients with PD was associated with increased risk of CVR. Increased risk of CVR was not associated with the use of non-ergot DAs. [ABSTRACT FROM AUTHOR]

To evaluate the long-term effects of entacapone on both mean daily ‘on’ time and health-related quality of life (QoL) in patients with Parkinson's disease (PD) experiencing ‘end-of-dose’ motor fluctuations and the benefits of an early therapeutic intervention. A prospective, multicenter, observational, 12-month study was performed with an initial 3-month intervention phase, consisting of a phone call to half of the patients from randomly selected investigators to assess if dose adjustment was necessary. Effectiveness was determined by home diaries (‘on’ time), subscales II and III of the Unified Parkinson's Disease Rating Scale (UPDRS), and the Parkinson's Disease Questionnaire (PDQ-8). After 3 months of treatment, 4.0% of the intervention group patients discontinued the study, versus 18.4% in the control group ( P < 0.01). The improvement in ‘on’ time was significantly increased since the 3-month visit (21%, P < 0.0001) until the end of the study (23% at 12 months, P < 0.0001). Entacapone also induced significant reductions in the UPDRS scores for subscales II and III and in the PDQ-8 score. 11.2% of patients experienced at least one adverse reaction. This study confirms the effectiveness of entacapone in reducing motor fluctuations by increasing ‘on’ time, and in improving QoL of PD patients. An early adjustment of entacapone and levodopa doses reduces the number of treatment discontinuations during the first months of treatment. [ABSTRACT FROM AUTHOR]

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the 'gold standard' against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy. © 2004 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives – To describe the clinical and neurophysiological findings in a case of hemimasticatory spasm (HMS) followed during 14 years of evolution. Material and methods – A woman suffered from very frequent paroxysmal episodes of painful involuntary occlusion of the jaw. Neurophysiological studies were performed at the 3, 12 and 14 years after the onset of symptoms. They included a needle electromyographic (EMG) evaluation of the main jaw closing and opening muscles, the jaw reflex (JR), the masseteric silent period (MSP) and the masseteric inhibitory reflex (MIR). Results – Clinical symptoms remained unchanged throughout the period of observation. Conventional EMG never disclosed neurogenic signs. Voluntary closure of the jaw systematically provoked an abnormal activity with muscle cramps characteristics, restricted to the left masseter muscle. Left JR response was normal in the first evaluation and became delayed and of reduced amplitude in the second. The MSP and MIR were abolished on the left side during the spasmodic episodes whereas they were strictly normal out of them. The MIR abnormalities showed the characteristic pattern of an efferent lesional type. Conclusion – Hemimasticatory spasm probably is the consequence of an abnormal trigeminal hyperexcitability likely induced by the demyelinating lesion of its peripheral motor pathway. The main neurophysiological abnormalities may persist unmodified over a long course of the disease and allow the differential diagnosis of HMS from oromandibular dystonia and temporomandibular dysfunction (TMD). [ABSTRACT FROM AUTHOR]

To identify putative risk factors for levodopa-induced dyskinesias we studied the effect of several clinical variables on the occurrence of dyskinesias in a series of 168 consecutive patients with Parkinson’s disease treated for at least 6 months with levodopa. Of these, 108 (64%) developed dyskinesias after a mean duration of levodopa treatment of 51.4 ± 43.3 months. Patients tended to suffer dyskinesias on the side of the body first affected by Parkinson’s disease. The overall probability of developing dyskinesias increased with levodopa treatment duration, about 10% per year during the first 7 years. Univariate and multivariate logistic regression analysis identified the age at onset of Parkinson’s disease (OR 0.923; 95% CI 0.883–0.964) and the initial levodopa dose (mean dose of the first 6 months of treatment; OR 1.004; 95% CI 1.002–1.006) as the main independent predictors. Survival curves showed that onset of Parkinson’s disease at age 50 years or before (logrank, P < 0.05) and initial levodopa treatment with more than 600 mg/day (logrank, P < 0.05) were associated with a higher risk for the appearance of dyskinesias. [ABSTRACT FROM AUTHOR]

The natural history and response to different treatments have been evaluated in 264 patients with blepharospasm. The mean age of onset was 55.8 years and there was a female preponderance of 1.8 to 1. Dystonia elsewhere was found in 78% of patients, usually in the cranial-cervical region, and appeared to follow a somatotopic progression. A family history of blepharospasm or dystonia elsewhere was found in 9.5% of cases, which suggests a genetic predisposition. Ocular lesions preceded the onset of blepharospasm in 12.1% of cases. The response to drugs was inconsistent, although initial improvement was experienced by one fifth of patients treated with anticholinergics. Twenty-nine bilateral facial nerve avulsion operations were performed with benefit in 27 cases; but recurrences appeared in 22, on average one year after surgery. Botulinum toxin injections were performed in 151 patients. Significant improvement was achieved in 118 cases. Mean duration of benefit was 9.2 weeks. Transient ptosis and diplopia were the commonest side effects. [ABSTRACT FROM AUTHOR]

Conversion from standard levodopa to Sinemet CR was performed in a series of 450 patients with Parkinson’s disease. Of these, 299 experienced motor complications (group A) and 151 showed stable motor response (group B). There was significant improvement in various parameters of efficacy (Unified Parkinson’s Disease Rating Scale, Hoehn-Yahr staging, Schwab-England scale) particularly in those related to functional aspects such as activities of daily living of the Unified Parkinson’s Disease Rating Scale, sleep questionnaires and the Nottingham Health Profile. Adverse effects were usually mild or moderate, and only 10% of patients discontinued Sinemet CR due to side effects. Sinemet CR treatment was preferred by 81% of patients in group A and by 73.8% of patients in group B. [ABSTRACT FROM AUTHOR]

The article offers information on two patients who developed stiff leg syndrome which is an uncommon focal variant of the stiff person syndrome after epidural anesthesia. Topics include antiglutamic acid decarboxylase antibodies, continuous motor unit activity, epidural anesthesia, and stiff limb syndrome.

A letter to the editor is presented about intraoperative microrecording under general anesthesia with bispectral analysis monitoring in a case of deep brain stimulation surgery for Parkinson's disease.

Discusses the management of adult spasticity. Clinical characteristics of the disease; Pathophysiology of the disease; Need to treat spasticity by a multidisciplinary team.