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The aim of this study is to describe the kinematic gait characteristics of straight line walk in clinically sound dairy cows using body mounted Inertial Measurement Units (IMUs) at multiple anatomical locations. The temporal parameters used are speed and non-speed normalized stance duration, bipedal and tripedal support durations, maximal protraction and retraction angles of the distal limbs and vertical displacement curves of the upper body. Gait analysis was performed by letting 17 dairy cows walk in a straight line at their own chosen pace while equipped with IMU sensors on tubera sacrale, left and right tuber coxae (LTC and RTC), back, withers, head, neck and all four lower limbs. Data intervals with stride by stride regularity were selected based on video data. For temporal parameters, the median was calculated and 95% confidence intervals (CI) were estimated based on linear mixed model (LMM) analysis, while for limb and vertical displacement curves, the median and most typical curves were calculated. The temporal parameters and distal limb angles showed consistent results with low variance and LMM analysis showed non-overlapping CI for all temporal parameters. The distal limb angle curves showed a larger and steeper retraction angle range for the distal front limbs compared with the hind limbs. The vertical displacement curves of the sacrum, withers, LTC and RTC showed a consistent sinusoidal pattern while the head, back and collar curves were less consistent and showed more variation between and within cows. This kinematic description might allow to objectively differentiate between normal and lame gait in the future and determine the best anatomical location for sensor attachment for lameness detection purposes. [ABSTRACT FROM AUTHOR]

Background and purpose: Functional movement disorders (FMDs) pose a diagnostic challenge for clinicians. Over the years several associated features have been shown to be suggestive for FMDs. Which features mentioned in the literature are discriminative between FMDs and non‐FMDs were examined in a large cohort. In addition, a preliminary prediction model distinguishing these disorders was developed based on differentiating features. Method: Medical records of all consecutive patients who visited our hyperkinetic outpatient clinic from 2012 to 2019 were retrospectively reviewed and 12 associated features in FMDs versus non‐FMDs were compared. An independent t test for age of onset and Pearson chi‐squared analyses for all categorical variables were performed. Multivariate logistic regression analysis was performed to develop a preliminary predictive model for FMDs. Results: A total of 874 patients were eligible for inclusion, of whom 320 had an FMD and 554 a non‐FMD. Differentiating features between these groups were age of onset, sex, psychiatric history, family history, more than one motor phenotype, pain, fatigue, abrupt onset, waxing and waning over long term, and fluctuations during the day. Based on these a preliminary predictive model was computed with a discriminative value of 91%. Discussion: Ten associated features are shown to be not only suggestive but also discriminative between hyperkinetic FMDs and non‐FMDs. Clinicians can use these features to identify patients suspected for FMDs and can subsequently alert them to test for positive symptoms at examination. Although a first preliminary model has good predictive accuracy, further validation should be performed prospectively in a multi‐center study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

For gait classification, hoof-on and hoof-off events are fundamental locomotion characteristics of interest. These events can be measured with inertial measurement units (IMUs) which measure the acceleration and angular velocity in three directions. The aim of this study was to present two algorithms for automatic detection of hoof-events from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. Seven Warmblood horses were equipped with two wireless IMUs, which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted on a lead over a force plate for internal validation. The agreement between the algorithms for the acceleration and angular velocity signals with the force plate was evaluated by Bland Altman analysis and linear mixed model analysis. These analyses were performed for both hoof-on and hoof-off detection and for both algorithms separately. For the hoof-on detection, the angular velocity algorithm was the most accurate with an accuracy between 2.39 and 12.22 ms and a precision of around 13.80 ms, depending on gait and hoof. For hoof-off detection, the acceleration algorithm was the most accurate with an accuracy of 3.20 ms and precision of 6.39 ms, independent of gait and hoof. These algorithms look highly promising for gait classification purposes although the applicability of these algorithms should be investigated under different circumstances, such as different surfaces and different hoof trimming conditions. [ABSTRACT FROM AUTHOR]

A prolonged break-over phase might be an indication of a variety of musculoskeletal disorders and can be measured with optical motion capture (OMC) systems, inertial measurement units (IMUs) and force plates. The aim of this study was to present two algorithms for automatic detection of the break-over phase onset from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. The performance of these algorithms was evaluated by internal validation with an OMC system and a force plate separately. Seven Warmblood horses were equipped with two wireless IMUs which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted over a force plate for internal validation while simultaneously the 3D position of three reflective markers, attached to lateral heel, lateral toe and lateral coronet of each hoof, were measured by six infrared cameras of an OMC system. The performance of the algorithms was evaluated by linear mixed model analysis. The acceleration algorithm was the most accurate with an accuracy between -9 and 23 ms and a precision around 24 ms (against OMC system), and an accuracy between -37 and 20 ms and a precision around 29 ms (against force plate), depending on gait and hoof. This algorithm seems promising for quantification of the break-over phase onset although the applicability for clinical purposes, such as lameness detection and evaluation of trimming and shoeing techniques, should be investigated more in-depth. [ABSTRACT FROM AUTHOR]

Objective: To explore driving performance and driving safety in patients with cervical dystonia (CD) on a simulated lane tracking, intersections and highway ride and to compare it to healthy controls. Design: This study was performed as an explorative between groups comparison. Participants: Ten CD patients with idiopathic CD, 30 years or older, stable on botulinum toxin treatment for over a year, holding a valid driver's license and being an active driver were compared with 10 healthy controls, matched for age and gender. Main outcome measures: Driving performance and safety, measured by various outcomes from the simulator, such as the standard deviation of the lateral position on the road, rule violations, percentage of line crossings, gap distance, and number of collisions. Fatigue and driving effort were measured with the Borg CR-10 scale and self-perceived fitness to drive was assessed with Fitness to Drive Screening. Results: Except for a higher percentage of line crossings on the right side of the road by controls (median percentage 2.30, range 0.00–37.00 vs. 0.00, range 0.00–9.20, p = 0.043), no differences were found in driving performance and driving safety during the simulator rides. Fatigue levels were significantly higher in CD patients just before (p = 0.005) and after (p = 0.033) the lane tracking ride (patients median fatigue levels before 1.5 (range 0.00–6.00) and after 1.5 (range 0.00–7.00) vs. controls median fatigue levels before and after 0.00 (no range). No significant differences were found on self-perceived fitness to drive. Conclusion: In patients with CD there were no indications that driving performance or driving safety were significant different from healthy controls in a simulator. Patients reported higher levels of fatigue both before and after driving compared to controls in accordance with the non-motor symptoms known in CD. [ABSTRACT FROM AUTHOR]

While fatigue is found to be an impairing symptom in functional motor disorders (FMD) in clinical practice, scientific evidence is lacking. We investigated fatigue severity and subtypes in FMD compared to organic neurological disease. Furthermore, the role of fatigue within FMD and its impact on quality of life and self-rated health were investigated. Data from 181 patients participating in the self-help on the internet for functional motor disorders, randomised Trial were included. Data from 217 neurological controls with neuromuscular disorders (NMD) originated from a historical cohort. Fatigue was measured using the checklist individual strength (CIS). Motor symptom severity, depression and anxiety were correlated to fatigue. For multivariable regression analyses, physical functioning and pain were additionally taken into account. Severe fatigue was, respectively, present in 78 and 53% of FMD and NMD patients (p < 0.001). FMD patients scored higher than NMD patients on all fatigue subdomains (p < 0.001). In the FMD group, fatigue subdomains were correlated to depression, anxiety and partly to motor symptom severity. Quality of life was negatively associated with fatigue [OR 0.93 (0.90-0.96), p < 0.001] and depression [OR 0.87 (0.81-0.93), p < 0.001], but not self-rated motor symptom severity. Self-rated health was negatively associated with fatigue [OR 0.92 (0.88-0.96), p < 0.001] and pain [OR 0.98 (0.97-0.99), p < 0.001]. Fatigue was found to be a prevalent problem in FMD, more so than in organic neurological disease. It significantly affected quality of life and self-rated health, while other factors such as motor symptom severity did not. Fatigue should be taken into account in clinical practice and treatment trials. [ABSTRACT FROM AUTHOR]

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

Background: Cervical dystonia (CD) is often accompanied by depressive symptoms, anxiety, and jerks/tremor. The dopamine transporter (DAT) binding is related with both depressive symptoms and jerks/tremor in CD. Serotonergic and dopaminergic systems are closely related. As serotonin is involved in the pathophysiology of psychiatric symptoms and jerks, we expected an altered serotoninergic system in CD. We hypothesized that CD is associated with reduced serotonin transporter (SERT) binding, more specific that SERT binding is lower in CD patients with psychiatric symptoms and/or jerks/tremor compared to those without, and to controls. The balance between SERT and DAT binding can be altered in different CD phenotypes. Results: In 23 CD patients and 14 healthy controls, SERT binding in the diencephalon/midbrain was assessed using [I]FP-CIT SPECT, with a brain-dedicated system. The specific to non-specific binding ratio (binding potential; BP) to SERT was the main outcome measure. There was a clear trend towards reduced SERT BP in CD patients with psychiatric symptoms compared to those without ( p = 0.05). There was no correlation between SERT binding and dystonia, jerks, or anxiety. There was a significant positive correlation between extrastriatal SERT and striatal DAT BP in CD patients with jerks, but not in patients without jerks. Conclusion: CD patients with psychiatric symptoms have lower SERT binding in the midbrain/diencephalon, while dystonia and jerks appear unrelated to SERT binding. The balance between extrastriatal SERT and striatal DAT binding is different in CD with and without jerks. [ABSTRACT FROM AUTHOR]

Botulinum toxin (BoNT) injections in the dystonic muscles is the preferred treatment for Cervical Dystonia (CD), but the proper identification of the dystonic muscles remains a challenge. Previous studies showed decreased 8-14 Hz autospectral power in the electromyography (EMG) of splenius muscles in CD patients. Cumulative distribution functions (CDF's) of dystonic muscles showed increased CDF10 values, representing increased autospectral powers between 3 and 10 Hz, relative to power between 3 and 32 Hz. In this study, we evaluated both methods and investigated the effects of botulinum toxin. Intramuscular EMG recordings were obtained from the splenius, semispinalis, and sternocleidomastoid muscles during standardized isometric tasks in 4 BoNT-naïve CD patients, 12 BoNT-treated patients, and 8 healthy controls. BoNT-treated patients were measured 4-7 weeks after their last BoNT injections and again after 11-15 weeks. We found significantly decreased 8-14 Hz autospectral power in splenius muscles, but not in the semispinalis and sternocleidomastoid muscles of CD patients when compared to healthy controls. CDF10 analysis was superior in demonstrating subtle autospectral changes, and showed increased CDF10 values in all studied muscles of CD patients. These results did not change significantly after BoNT injections. Further studies are needed to investigate the origin of these autospectral changes in dystonia patients, and to assess their potential in muscle selection for BoNT treatment. [ABSTRACT FROM AUTHOR]

Background and purpose Huntington's disease ( HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterized by chorea. Dystonia is also recognized as part of the HD motor phenotype, although little work detailing its prevalence, distribution, severity and impact on functional capacity has been published to date. Methods Patients (>18 years of age) were recruited from the Cardiff (UK) HD clinic, each undergoing a standardized videotaped clinical examination and series of functional assessment questionnaires (Unified Huntington's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale and modified version of the Toronto Western Spasmodic Torticollis Rating Scale). The presence and severity of dystonia were scored by four independent neurologists using the Burke-Fahn-Marsden Dystonia Rating Scale and Unified Huntington's Disease Rating Scale. Statistical analysis included Fisher's exact test, Wilcoxon test, anova and calculation of correlation coefficients where appropriate. Results Forty-eight patients [91% (48/53)] demonstrated evidence of dystonia, with the highest prevalence in the left upper limb ( n = 44, 83%), right upper limb most severely affected and eyes least affected. Statistically significant positive correlations ( P < 0.05) were observed between dystonia severity and increasing HD disease stage and motor disease duration. Deterioration in functional capacity also correlated with increasing dystonia severity. No significant relationship was observed with age at motor symptom onset or CAG repeat length. Conclusions We report a high prevalence of dystonia in adult patients with HD, with worsening dystonia severity with increasing HD disease stage and motor disease duration. The recognition and management of dystonic symptoms in routine clinical practice will aid overall symptomatic treatment and functional improvement. [ABSTRACT FROM AUTHOR]

Purpose: Cervical dystonia (CD) is associated with tremor/jerks (50%) and psychiatric complaints (17-70%). The dopaminergic system has been implicated in the pathophysiology of CD in animal and imaging studies. Dopamine may be related to the motor as well as non-motor symptoms of CD. CD is associated with reduced striatal dopamine D (D2/3) receptor and increased dopamine transporter (DAT) binding. There are differences in the dopamine system between CD patients with and without jerks/tremor and psychiatric symptoms. Methods: Patients with CD and healthy controls underwent neurological and psychiatric examinations. Striatal DAT and D2/3 receptor binding were assessed using [I]FP-CIT and [I]IBZM SPECT, respectively. The ratio of specific striatal to non-specific binding (binding potential; BP) was the outcome measure. Results: Twenty-seven patients with CD and 15 matched controls were included. Nineteen percent of patients fulfilled the criteria for a depression. Striatal DAT BP was significantly lower in depressed versus non-depressed CD patients. Higher DAT BP correlated significantly with higher scores on the Unified Myoclonus Rating Scale (UMRS). The striatal D2/3 receptor BP in CD patients showed a trend towards lower binding compared to controls. The D2/3 BP was significantly lower in depressed versus non-depressed CD patients. A significant correlation between DAT and D2/3R BP was found in both in patients and controls. Conclusions: Alterations of striatal DAT and D2/3 receptor binding in CD patients are related mainly to depression. DAT BP correlates significantly with scores on the UMRS, suggesting a role for dopamine in the pathophysiology of tremor/jerks in CD. [ABSTRACT FROM AUTHOR]

The purpose of this retrospective cohort study was to (a) describe the clinical presentation of femoroacetabular impingement ( FAI) and hip labral pathology; (b) describe the accuracy of patient history and physical tests for FAI and labral pathology as confirmed by hip arthroscopy. Patients (18-65 years) were included if they were referred to a physical therapist to gather pre-operative data and were then diagnosed during arthroscopy. Results of pre-operative patient history and physical tests were collected and compared to arthroscopy. Data of 77 active patients (mean age: 37 years) were included. Groin as main location of pain, the Anterior Impingement test ( AIT), Flexion-Abduction-External Rotation ( FABER) test, and Fitzgerald test had a high sensitivity (range 0.72-0.91). Sensitivity increased when combining these tests (0.97) as either groin as main location of pain and a positive FABER test or a positive AIT and a positive FABER test were the shortest most sensitive combinations. The results of this study point out that in clinical practice absence of groin as main location of pain combined with a negative FABER test or the combination of a negative AIT and a negative FABER test are suggested to rule out the diagnosis of symptomatic FAI and/or labral pathology. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus.Methods: Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed.Results: A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities.Conclusions: Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin of myoclonus was demonstrated. Our data suggest that myoclonus may be overlooked in patients with NP-C. All patients scored significantly lower on physical domains of HRQoL. Symptomatic treatment of movement disorders may improve physical functioning and subsequently HRQoL. [ABSTRACT FROM AUTHOR]

The physical examination findings of early posthypoxic myoclonus (PHM) are associated with poor prognosis. Recent findings indicate that patients with multifocal PHM, assumed to have a cortical origin, have a comparable outcome to resuscitated patients without PHM. Generalized PHM, assumed to have a subcortical myoclonus origin, is still associated with a bad clinical outcome. It is not known whether the electroencephalographic (EEG) findings differ between the multifocal and generalized myoclonus groups nor is the clinical significance clearly defined. Forty-three patients with PHM were retrospectively derived from an EEG database. Patients were categorized as having multifocal (i), generalized (ii), or undetermined (iii) PHM. Outcome was expressed in cerebral performance category scores. The EEG background was categorized into isoelectric (I), low voltage (II), burst suppression (III), status epilepticus (SE; IV), diffuse slowing (V), and mild encephalopathic or normal (VI). 17 patients had generalized PHM and 23 had multifocal PHM (3 undetermined). The EEG showed more SE in generalized compared to multifocal PHM (64% vs 13%, P < .001). Diffuse slowing was more often present in multifocal PHM (52% vs 17%, P < .05). Early-onset myoclonus occurred significantly more often in generalized PHM, and early generalized PHM was invariantly associated with poor outcome. In conclusion, patients with generalized PHM showed more SE. These EEG findings might be either subcortical corollaries or primarily cortical phenomena. Our retrospective results conflict with currently used clinical criteria for myoclonus classification, and we suggest that more refined difference may be needed for accurate assessment of PHM. To better understand PHM, prospective research with standardized clinical assessment and quantitative EEG analysis is needed. [ABSTRACT FROM AUTHOR]

Background: Femoroacetabular impingement has been recognized as a common cause of hip pain and dysfunction, especially in athletes. Femoroacetabular impingement can now be better treated by hip arthroscopy but it is unclear what postoperative rehabilitation of hip arthroscopy should look like. Several rehabilitation protocols have been described, but none presented clinical outcome data. These protocols also differ in frequency, duration and level of supervision. We developed a rehabilitation protocol with supervised physical therapy which showed good clinical results and is considered usual care in our treatment center. However, it is unknown whether, due to the relatively young age and low complication rate of hip arthroscopy patients, rehabilitation based on self-management might lead to similar results. The aims of this pilot study are (1) to determine feasibility and acceptability of the self-management intervention, (2) to obtain a preliminary estimate of the difference in effect between physical therapy aimed at self-management versus usual care physical therapy in patients who undergo hip arthroscopy for femoroacetabular impingement.Methods/design: Thirty participants (aged 18-50 years) scheduled for hip arthroscopy will be included and randomized (after surgery) to either self-management or usual care physical therapy in this assessor-blinded randomized controlled trial. After surgery, the self-management group will perform a home-based exercise program three times a week and will receive physical therapy treatment once every 2 weeks for 14 weeks. The usual care group will receive physical therapy treatment twice a week for 14 weeks and will perform an additional home-based exercise program once a week. Assessment will occur preoperatively and at 6, 14, 26 and 52 weeks after surgery. Primary outcomes are feasibility, acceptability and preliminary effectiveness. Feasibility and acceptability will be determined by the willingness to enroll, recruitment rate, adherence to treatment, patient satisfaction, drop-out rate and adverse events. Preliminary effectiveness will be determined using the following outcomes: the International Hip Outcome Tool 33 and hip functional performance as measured with the Single Leg Squat Test 14 weeks after surgery.Discussion: The results of this study will be used to help decide on the need, feasibility and acceptability of a large-scale randomized controlled trial.Trial Registration: This protocol was registered with the Dutch Trial Registry (NTR5168) on 8 May 2015. [ABSTRACT FROM AUTHOR]

Background/aim: To recommend Patient-Reported Outcome (PRO) questionnaires to measure hip and groin disability in young-aged to middle-aged adults.Methods: A systematic review was performed in June 2014. The methodological quality of the studies included was determined using the COnsensus-based Standards for the selection of health Measurement INstruments list (COSMIN) together with standardised evaluations of measurement properties of each PRO.Results: Twenty studies were included. Nine different questionnaires for patients with hip disability, and one for hip and groin disability, were identified. Hip And Groin Outcome Score (HAGOS), Hip Outcome Score (HOS), International Hip Outcome Tool-12 (IHOT-12) and IHOT-33 were the most thoroughly investigated PROs and studies including these PROs reported key aspects of the COSMIN checklist. HAGOS and IHOT-12 were based on studies with the least ratings of poor study methodology (23% and 31%, respectively), whereas IHOT-33 and HOS had a somewhat larger distribution (46%). These PROs all contain adequate measurement qualities for content validity (except HOS), test-retest reliability, construct validity, responsiveness and interpretability. No information or poor quality rating on methodological aspects made it impossible to fully evaluate the remaining PROs at present.Conclusions: HAGOS, HOS, IHOT-12 and IHOT-33 can be recommended for assessment of young-aged to middle-aged adults with pain related to the hip joint, undergoing non-surgical treatment or hip arthroscopy. At present, HAGOS is the only PRO also aimed for young-aged to middle-aged adults presenting with groin pain and is recommended for use in this population.Trial Registration Number: CRD42014009995. [ABSTRACT FROM AUTHOR]

Background:Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.Methods:The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).Results:High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).Conclusions:Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC. [ABSTRACT FROM AUTHOR]

Objectives: To assess the feasibility of dual energy computed tomography (DE-CT) in intra-arterially treated acute ischaemic stroke patients to discriminate between contrast extravasation and intracerebral haemorrhage. Methods: Thirty consecutive acute ischaemic stroke patients following intra-arterial treatment were examined with DE-CT. Simultaneous imaging at 80 kV and 140 kV was employed with calculation of mixed images. Virtual unenhanced non-contrast (VNC) images and iodine overlay maps (IOM) were calculated using a dedicated brain haemorrhage algorithm. Mixed images alone, as 'conventional CT', and DE-CT interpretations were evaluated and compared with follow-up CT. Results: Eight patients were excluded owing to a lack of follow-up or loss of data. Mixed images showed intracerebral hyperdense areas in 19/22 patients. Both haemorrhage and residual contrast material were present in 1/22. IOM suggested contrast extravasation in 18/22 patients; in 16/18 patients this was confirmed at follow-up. The positive predictive value (PPV) of mixed imaging alone was 25 %, with a negative predictive value (NPV) of 91 % and accuracy of 63 %. The PPV for detection of haemorrhage with DE-CT was 100 %, with an NPV of 89 % and accuracy improved to 89 %. Conclusions: Dual energy computed tomography improves accuracy and diagnostic confidence in early differentiation between intracranial haemorrhage and contrast medium extravasation in acute stroke patients following intra-arterial revascularisation. Key Points: • Contrast material and haemorrhage have similar density on conventional 120-kV CT. • Contrast material hinders interpretation of CT in stroke patients after recanalisation. • Iodine and haemorrhage have different attenuation at lower kVs. • Dual energy CT improves accuracy in early differentiation of haemorrhage and contrast extravasation. • Early differentiation between iodine and haemorrhage helps to initiate therapy promptly. [ABSTRACT FROM AUTHOR]

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Focal dystonia is a common, invalidating neurologic condition characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures in one body part. Currently, botulinum toxin is the treatment of first choice. We performed a systematic review towards the pharmaco-therapeutic and pharmaco-economic value of botulinum toxin as treatment for focal dystonia, which yielded the following results. Botulinum toxin is the most effective treatment for reducing dystonic symptoms measured with dystonia-specific and general questionnaires, and pain in patients with focal dystonia. Seventy-one percent of patients with cervical dystonia had a reduction in neck pain compared to 12 % in placebo groups. Adverse events occur in 58 % of patients during treatment with botulinum toxin compared to 46 % treated with placebo. Especially dry mouth, neck weakness, dysphagia, and voice changes are common. Adverse events are usually mild and self-limiting. Health-related quality of life, measured with the SF-36 is 20-50 points lower in patients with focal dystonia compared to controls and the effect of botulinum toxin on health-related quality of life is unclear. Botulinum toxin treatment is expensive because the drug itself is expensive. Yearly costs for treating a patient with focal dystonia with botulinum toxin range from EUR 347 to EUR 3,633 and the gain in QALYs with BTX treatment is small. Focal dystonia impairs the productivity and the ability to work. At start of botulinum toxin treatment only 47-50 % was working. Botulinum toxin partly improves this. Overall, we conclude that botulinum toxin is an expensive drug with good effects. From a societal perspective, the costs may well weigh up to the regained quality of life. However, the available literature concerning costs, health-related quality of life and labor participation is very limited. An extensive cost-effectiveness study should be performed incorporating all these aspects. [ABSTRACT FROM AUTHOR]

Background: Lymph node (LN) yield in colon cancer resection specimens is an important indicator of treatment quality and has especially in early-stage patients therapeutic implications. However, underlying disease mechanisms, such as microsatellite instability (MSI), may also influence LN yield, as MSI tumors are known to exhibit more prominent lymphocytic antitumor reactions. The aim of the present study was to investigate the association of LN yield, MSI status, and recurrence rate in colon cancer. Methods: Clinicopathological data and tumor samples were collected from 332 stage II and III colon cancer patients. DNA was isolated and PCR-based MSI analysis performed. LN yield was defined as 'high' when 10 or more LNs were retrieved and 'low' in case of fewer than 10 LNs. Results: Tumors with high LN yield were significantly associated with the MSI phenotype (high LN yield: 26.3% MSI tumors vs low LN yield: 15.1% MSI tumors; P = .01), mainly in stage III disease. Stage II patients with high LN yield had a lower recurrence rate compared with those with low LN yield. Patients with MSI tumors tended to develop fewer recurrences compared with those with MSS tumors, mainly in stage II disease. Conclusions: In the present study, high LN yield was associated with MSI tumors, mainly in stage III patients. Besides adequate surgery and pathology, high LN yield is possibly a feature caused by biologic behavior of MSI tumors. [ABSTRACT FROM AUTHOR]

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder characterized by myoclonic jerks and dystonic postures or movements. Morphometric studies have been performed in other, mainly heterogenous, types of dystonia producing conflicting results. However, all these studies agree on abnormalities in sensorimotor structures, mainly in the basal ganglia. We aimed to study gray matter (GM) volumes in sensorimotor brain structures with magnetic resonance imaging (MRI) in a genetically homogeneous form of dystonia, M-D . Twenty-five clinically affected DYT11 mutation carriers (MC) and 25 matched control subjects were studied using T1-weighted 3D anatomical images of the entire brain, obtained with a 3.0 Tesla MRI. MC were clinically scored using the Burke Fahn Marsden dsytonia rating scale (BFMDRS) and the unified myoclonus rating scale (UMRS). GM volumes in sensorimotor cortices and basal ganglia of patients and controls were compared, and multiple regression analyses were used to correlate the GM volumes of patients with the clinical rating scales BFMDRS and UMRS. No significant differences were found between groups, but dystonia severity in MC was strongly correlated with increased GM volume in bilateral putamina. This study provides further evidence for the involvement of putamina as important motor structures in the pathophysiology of (myoclonus-) dystonia. Changes in these structures are associated with the severity of dystonia. [ABSTRACT FROM AUTHOR]

Tijssen MJA, Van Os J, Wittchen HU, Lieb R, Beesdo K, Wichers M. Risk factors predicting onset and persistence of subthreshold expression of bipolar psychopathology among youth from the community Objective: To examine factors increasing the risk for onset and persistence of subthreshold mania and depression. Method: In a prospective cohort community study, the association between risk factors [a family history of mood disorders, trauma, substance use, attention-deficit/hyperactivity disorder (ADHD) and temperamental/personality traits] and onset of manic/depressive symptoms was determined in 705 adolescents. The interaction between baseline risk factors and baseline symptoms in predicting 8-year follow-up symptoms was used to model the impact of risk factors on persistence. Results: Onset of manic symptoms was associated with cannabis use and novelty seeking (NS), but NS predicted a transitory course. Onset of depressive symptoms was associated with a family history of depression. ADHD and harm avoidance (HA) were associated with persistence of depressive symptoms, while trauma and a family history of depression predicted a transitory course. Conclusion: Different risk factors may operate during onset and persistence of subthreshold mania and depression. The differential associations found for mania and depression dimensions suggest partly different underlying mechanisms. [ABSTRACT FROM AUTHOR]

In a literature survey, 341 patients with primary and 109 with secondary dystonias treated with deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) were identified. In general, the outcomes for primary dystonias were more favourable compared to the secondary forms. For some secondary dystonias – like tardive dystonia, myoclonus-dystonia (M-D), NBIA (PANK2), the outcome was very good. Only for the primary generalized dystonias, the efficacy of GPi-DBS has been confirmed in randomised controlled trials. Predictors of outcome are the experience and dedication of the stereotactic team, the selection of patients – the diagnosis and pre-operative screening – and the quality of the post-operative care. Predictors of negative outcome are long duration of the disease – with contractures or scoliosis – and concomitant symptoms like spasticity and cerebellar dysfunction. More studies are required to establish the role of GPi-DBS in the treatment of secondary dystonias. [ABSTRACT FROM AUTHOR]

In dystonia, both sensory malfunctioning and an abnormal intermuscular low-frequency drive of 3–7 Hz have been found, although cause and effect are unknown. It is hypothesized that sensory processing is primarily disturbed and induces this drive. Accordingly, experimenter-controlled sensory input should be able to influence the frequency of the drive. In six genetically confirmed myoclonus-dystonia (MD) patients and six matched controls, the low-frequency drive was studied with intermuscular coherence analysis. External perturbations were applied mechanically to the wrist joint in small frequency bands (0–4, 4–8 and 8–12 Hz; ‘angle protocol) and at single frequencies (1, 5, 7 and 9 Hz; ‘torque’ protocol). The low-frequency drive was found in the neck muscles of 4 MD patients. In these patients, its frequency did not shift due to the perturbation. In the torque protocol, the externally applied frequencies could be detected in all controls and in the two patients without the common drive. The common low-frequency drive was not be affected by external perturbations in MD patients. Furthermore, the torque protocol did not induce intermuscular coherences at the applied frequencies in these patients, as was the case in healthy controls and in patients without the drive. This suggests that the dystonic 3–7 Hz drive is caused by a sensory-independent motor drive and sensory malfunctioning in MD might rather be a consequence than a cause of dystonia. [ABSTRACT FROM AUTHOR]

Background. Reported rates of bipolar syndromes are highly variable between studies because of age differences, differences in diagnostic criteria, or restriction of sampling to clinical contacts. Method. In 1395 adolescents aged 14-17 years, DSM-IV (hypo)manic episodes (manic and hypomanic episodes combined), use of mental health care, and five ordinal subcategories representing the underlying continuous score of (hypo)manic symptoms ('mania symptom scale ') were measured at baseline and approximately 1.5, 4 and 10 years later using the Munich-Composite International Diagnostic Interview (DIA-X/M-CIDI). Results. Incidence rates (IRs) of both (hypo)manic episodes and (hypo)manic symptoms (at least one DSM-IV core symptom) were far higher (714/105 person-years and 1720/105 person-years respectively) than traditional estimates. In addition, the risk of developing (hypo)manic episodes was very low after the age of 21 years [hazard ratio (HR) 0.031, 95% confidence interval (CI) 0.0050-0.19], independent of childhood disorders such as attention deficit hyperactivity disorder (ADHD). Most individuals with hypomanic and manic episodes were never in care (87% and 62% respectively) and not presenting co-morbid depressive episodes (69% and 60% respectively). The probability of mental health care increased linearly with the number of symptoms on the mania symptom scale. The incidence of the bipolar categories, in particular at the level of clinical morbidity, was strongly associated with previous childhood disorders and male sex. Conclusions. This study showed, for the first time, that experiencing (hypo)manic symptoms is a common adolescent phenomenon that infrequently predicts mental health care use. The findings suggest that the onset of bipolar disorder can be elucidated by studying the pathway from non-pathological behavioural expression to dysfunction and need for care. [ABSTRACT FROM AUTHOR]

Extrapontine myelinolysis (EPM) is a rare cause of parkinsonism. In this case report, we describe a 63-year-old woman with parkinsonism due to EPM after correction of hyponatremia. During a 4-year follow-up, both the clinical features of parkinsonism and the changes on magnetic resonance imaging resolved. Parkinsonism due to EPM should be recognized as it has a good prognosis. [ABSTRACT FROM AUTHOR]

The paroxysmal dyskinesias are a challenging group of movement disorders characterised by painless dystonic and/or choreiform movements. Lack of familiarity with their features and a normal neurological examination between attacks frequently cause diagnostic delays, or even the diagnosis of a non-organic disorder. They are classified by their mode of triggering, and also by the duration and frequency of attacks, effectiveness of medication, and any associated syndromes. Four subtypes are recognised: paroxysmal kinesigenic dyskinesia induced by sudden movement; paroxysmal non-kinesigenic dyskinesia precipitated by for instance alcohol or caffeine; paroxysmal exercise-induced dyskinesia triggered by longer lasting activity; and paroxysmal hypnogenic dyskinesia occurring during sleep. Here we will summarise the characteristics of the subtypes, discuss the differential diagnosis, genetic aspects and pathophysiology, and give practical advice on the diagnostic work-up and treatment. [ABSTRACT FROM AUTHOR]

To study striatal dopamine D2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus–dystonia (M–D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using 123I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. [ABSTRACT FROM AUTHOR]

T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT-PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about transplantation of human peripheral blood in fast platelet formation in NOD/SCID mice that is published within the issue.

A series of studies have been published that evaluate the chromosomal copy number changes of different tumor classes using array comparative genomic hybridization (array CGH); however, the chromosomal aberrations that distinguish the different tumor classes have not been fully characterized. Therefore, we performed a meta-analysis of different array CGH data sets in an attempt to classify samples tested across different platforms. As opposed to RNA expression, a common reference is used in dual channel CGH arrays: normal human DNA, theoretically facilitating cross-platform analysis. To this aim, cell line and primary cancer data sets from three different dual channel array CGH platforms obtained by four different institutes were integrated. The cell line data were used to develop preprocessing methods, which performed noise reduction and transformed samples into a common format. The transformed array CGH profiles allowed perfect clustering by cell line, but importantly not by platform or institute. The same preprocessing procedures used for the cell line data were applied to data from 373 primary tumors profiled by array CGH, including controls. Results indicated that there is no apparent feature related to the institute or platform and that array CGH allows for unambiguous cross-platform meta-analysis. Major clusters with common tissue origin were identified. Interestingly, tumors of hematopoietic and mesenchymal origins cluster separately from tumors of epithelial origin. Therefore, it can be concluded that chromosomal aberrations of tumors from hematopoietic and mesenchymal origin versus tumors of epithelial origin are distinct, and these differences can be picked up by meta-analysis of array CGH data. This suggests the possibility of prospectively using combined analysis of diverse copy number data sets for cancer subtype classification.Oncogene (2007) 26, 1499–1506. doi:10.1038/sj.onc.1209919; published online 28 August 2006 [ABSTRACT FROM AUTHOR]

Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (n = 246) resulted in three separate DLBCL groups partly overlapping with germinal centre B-lymphocytes versus activated B-cells like phenotype. One group with poor clinical outcome was characterised by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A second group, also with poor clinical outcome, was characterised by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The third group showing a favourable outcome was characterised by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterised either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralising the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL. [ABSTRACT FROM AUTHOR]

The use of next-generation sequencing to unravel new genes: overcoming challenges posed by rare neurological disorders such as myoclonus-dystonia The revolution in next-generation sequencing has brought to light detailed catalogues of genetic variation in both patients with disease and the general population [1]. Moreover, analysis of public RNA-seq databases shows that I KCNN2 i is highly expressed in the cerebellum (a region implicated in M-D pathophysiology) and gene co-regulation analysis reveals similarity between I KCNN2 i and other genes implicated in M-D pathophysiology such as I ANO3 i , I RELN i and I TUBB2B i [4]. [Extracted from the article]

Post-traumatic stress disorder (PTSD) patients are considered to have excessive EMG responses in the orbicularis oculi (OO) muscle and excessive autonomic responses to startling stimuli. The aim of the present study was to gain more insight into the pattern of the generalized auditory startle reflex (ASR). Reflex EMG responses to auditory startling stimuli in seven muscles rather than the EMG response of the OO alone as well as the psychogalvanic reflex (PGR) were studied in PTSD patients and healthy controls. Ten subjects with chronic PTSD (>3 months) and a history of excessive startling and 11 healthy controls were included. Latency, amplitude and duration of the EMG responses and the amplitude of the PGR to 10 auditory stimuli of 110 dB SPL were investigated in seven left-sided muscles. The size of the startle reflex, defined by the number of muscles activated by the acoustic stimulus and by the amplitude of the EMG response of the OO muscle as well, did not differ significantly between patients and controls. Median latencies of activity in the sternocleidomastoid (SC) (patients 80 ms; controls 54 ms) and the deltoid (DE) muscles (patients 113 ms; controls 69 ms) were prolonged significantly in PTSD compared to controls ( P<0.05). In the OO muscle, a late response (median latency in patients 308 ms; in controls 522 ms), probably the orienting reflex, was more frequently present in patients (56%) than in controls (12%). In patients, the mean PGR was enlarged compared to controls ( P<0.05). The size of the ASR response is not enlarged in PTSD patients. EMG latencies in the PTSD patients are prolonged in SC and DE muscles. The presence of a late response in the OO muscle discriminates between groups of PTSD patients with a history of startling and healthy controls. In addition, the autonomic response, i.e. the enlarged amplitude of the PGR can discriminate between these groups. [ABSTRACT FROM AUTHOR]

The article discusses various topics in physiology of megakaryocytopoiesis in relation to thrombopoietin (Tpo) in therapy and diagnostics to ex vivo generated cellular products. The author discusses the following topics: 1) Tpo in diagnostics 2) Bone marrow and megakaryocytopoietic assays in diagnostics 3) Use of Tpo/Mpl agonists in therapy and 4) Ex vivo expanded megakaryocytes for therapy.

The aim of the present study was to investigate the contribution of reciprocal inhibition to muscle tone by examining the transmission in the reciprocal inhibitory pathway in patients with a known defect in the glycine receptor. The study was performed in eight patients with hereditary hyperekplexia, six with the major form and two with the minor form of the disease. A mutation in the α1-subunit of the glycine receptor had been demonstrated in the patients with the major form, whereas no mutation was seen in the patients with the minor form. Disynaptic reciprocal inhibition, which is presumed to be mediated by glycine, was not seen in the patients with the major form of the disease, while it could be evoked in the patients with the minor form of the disease. Presynaptic inhibition, which is presumed to be mediated by GABA, was seen in both types of patients. It is concluded that the major form of hereditary hyperekplexia is associated with impaired transmission in glycinergic reciprocal inhibitory pathways. The findings demonstrate the importance of reciprocal inhibition for the muscle tone in man, and it is suggested that the impaired reciprocal inhibition seen in patients with a defect in the glycine receptor may contribute to the increased muscle stiffness that is observed in these patients. [ABSTRACT FROM AUTHOR]