Causes of failure of pallidal deep brain stimulation in cases with pre-operative diagnosis of isolated dystonia.

INTRODUCTION: Pallidal deep brain stimulation (GPi-DBS) is an effective therapy for isolated dystonia, but 10-20% of patients show improvement below 25-30%. We here investigated causes of insufficient response to GPi-DBS in isolated dystonia in a cross-sectional study. METHODS: Patients with isolated dystonia at time of surgery, and <30% improvement on the Burke-Fahn-Marsden dystonia-rating-scale (BFMDRS) after ≥6 months of continuous GPi-DBS were videotaped ON and OFF stimulation, and history, preoperative videos, brain MRI, medical records, stimulation settings, stimulation system integrity, lead location, and genetic information were obtained and reviewed by an expert panel. RESULTS: 22 patients from 11 centres were included (8 men, 14 women; 9 generalized, 9 segmental, 3 focal, 1 bibrachial dystonia; mean (range): age 48.7 (25-72) years, disease duration 22.0 (2-40) years, DBS duration 45.5 (6-131) months). Mean BFMDRS-score was 31.7 (4-93) preoperatively and 32.3 (5-101) postoperatively. Half of the patients (n = 11) had poor lead positioning alone or in combination with other problems (combined with: other disease n = 6, functional dystonia n = 1, other problems n = 2). Other problems were disease other than isolated inherited or idiopathic dystonia (n = 5), fixed deformities (n = 2), functional dystonia (n = 3), and other causes (n = 1). Excluding patients with poor lead location from further analysis, non-isolated dystonia accounted for 45.5%, functional dystonia for 27.3%, and fixed deformities for 18.2%. In patients with true isolated dystonia, lead location was the most frequent problem. CONCLUSION: After exclusion of lead placement and stimulation programming issues, non-isolated dystonia, functional dystonia and fixed deformities account for the majority of GPi-DBS failures in dystonia.

Third-Generation Light-Driven Symmetric Molecular Motors.

Symmetric molecular motors based on two overcrowded alkenes with a notable absence of a stereogenic center show potential to function as novel mechanical systems in the development of more advanced nanomachines offering controlled motion over surfaces. Elucidation of the key parameters and limitations of these third-generation motors is essential for the design of optimized molecular machines based on light-driven rotary motion. Herein we demonstrate the thermal and photochemical rotational behavior of a series of third-generation light-driven molecular motors. The steric hindrance of the core unit exerted upon the rotors proved pivotal in controlling the speed of rotation, where a smaller size results in lower barriers. The presence of a pseudo-asymmetric carbon center provides the motor with unidirectionality. Tuning of the steric effects of the substituents at the bridgehead allows for the precise control of the direction of disrotary motion, illustrated by the design of two motors which show opposite rotation with respect to a methyl substituent. A third-generation molecular motor with the potential to be the fastest based on overcrowded alkenes to date was used to visualize the equal rate of rotation of both its rotor units. The autonomous rotational behavior perfectly followed the predicted model, setting the stage for more advanced motors for functional dynamic systems.

An algorithm for calculating exam quality as a basis for performance-based allocation of funds at medical schools.

OBJECTIVE: The amendment of the Medical Licensing Act (ÄAppO) in Germany in 2002 led to the introduction of graded assessments in the clinical part of medical studies. This, in turn, lent new weight to the importance of written tests, even though the minimum requirements for exam quality are sometimes difficult to reach. Introducing exam quality as a criterion for the award of performance-based allocation of funds is expected to steer the attention of faculty members towards more quality and perpetuate higher standards. However, at present there is a lack of suitable algorithms for calculating exam quality. METHODS: In the spring of 2014, the students' dean commissioned the "core group" for curricular improvement at the University Medical Center in Rostock to revise the criteria for the allocation of performance-based funds for teaching. In a first approach, we developed an algorithm that was based on the results of the most common type of exam in medical education, multiple choice tests. It included item difficulty and discrimination, reliability as well as the distribution of grades achieved. RESULTS: This algorithm quantitatively describes exam quality of multiple choice exams. However, it can also be applied to exams involving short assay questions and the OSCE. It thus allows for the quantitation of exam quality in the various subjects and - in analogy to impact factors and third party grants - a ranking among faculty. CONCLUSION: Our algorithm can be applied to all test formats in which item difficulty, the discriminatory power of the individual items, reliability of the exam and the distribution of grades are measured. Even though the content validity of an exam is not considered here, we believe that our algorithm is suitable as a general basis for performance-based allocation of funds.

The role of mutations in COL6A3 in isolated dystonia.

Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.

Magnetic resonance-transcranial ultrasound fusion imaging: A novel tool for brain electrode location.

BACKGROUND: A combination of preoperative magnetic resonance imaging (MRI) with real-time transcranial ultrasound, known as fusion imaging, may improve postoperative control of deep brain stimulation (DBS) electrode location. Fusion imaging, however, employs a weak magnetic field for tracking the position of the ultrasound transducer and the patient's head. Here we assessed its feasibility, safety, and clinical relevance in patients with DBS. METHODS: Eighteen imaging sessions were conducted in 15 patients (7 women; aged 52.4 ± 14.4 y) with DBS of subthalamic nucleus (n = 6), globus pallidus interna (n = 5), ventro-intermediate (n = 3), or anterior (n = 1) thalamic nucleus and clinically suspected lead displacement. Minimum distance between DBS generator and magnetic field transmitter was kept at 65 cm. The pre-implantation MRI dataset was loaded into the ultrasound system for the fusion imaging examination. The DBS lead position was rated using validated criteria. Generator DBS parameters and neurological state of patients were monitored. RESULTS: Magnetic resonance-ultrasound fusion imaging and volume navigation were feasible in all cases and provided with real-time imaging capabilities of DBS lead and its location within the superimposed magnetic resonance images. Of 35 assessed lead locations, 30 were rated optimal, three suboptimal, and two displaced. In two cases, electrodes were re-implanted after confirming their inappropriate location on computed tomography (CT) scan. No influence of fusion imaging on clinical state of patients, or on DBS implantable pulse generator function, was found. CONCLUSIONS: Magnetic resonance-ultrasound real-time fusion imaging of DBS electrodes is safe with distinct precautions and improves assessment of electrode location. It may lower the need for repeated CT or MRI scans in DBS patients.

Cognitive outcome of pallidal deep brain stimulation for primary cervical dystonia: One year follow up results of a prospective multicenter trial.

BACKGROUND: Pallidal deep brain stimulation (DBS) is effective in alleviating motor symptoms of medication refractory cervical dystonia, but little is known about effects on cognitive functions. METHODS: As part of the first randomized, sham-controlled multicenter trial on DBS in medication-refractory primary cervical dystonia (ClinicalTrials.gov, number NCT00148889), a subgroup of 13 patients aged 39 to 69 underwent prospective neuropsychological long-term follow-up assessments. Various cognitive domains (memory, executive functions, attention, visual perception, mental arithmetic and verbal intelligence) were examined before and after 12 months of continuous DBS. RESULTS: Only the number of produced words in a verbal fluency task which included alternating categories decreased after stimulation (p = 0.020). All other cognitive domains remained unchanged. CONCLUSIONS: These findings indicate that long-term pallidal DBS for the treatment of primary cervical dystonia seems to be safe regarding global cognitive functioning.

Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia.

OBJECTIVES: Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in treatment-refractory dystonia, and the identification of factors predicting surgical outcome is needed to optimize patient selection. METHODS: In this retrospective multicenter study, GPi-DBS outcome of 8 patients with DYT6, 9 with DYT1, and 38 with isolated dystonia without known monogenic cause (non-DYT) was assessed at early (1-16 months) and late (22-92 months) follow-up using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. RESULTS: At early follow-up, mean reduction of dystonia severity was greater in patients with DYT1 (BFMDRS score: -60%) and non-DYT dystonia (-52%) than in patients with DYT6 dystonia (-32%; p = 0.046). Accordingly, the rate of responders was considerably lower in the latter group (57% vs >90%; p = 0.017). At late follow-up, however, GPi-DBS resulted in comparable improvement in all 3 groups (DYT6, -42%; DYT1, -44; non-DYT, -61%). Additional DBS of the same or another brain target was performed in 3 of 8 patients with DYT6 dystonia with varying results. Regardless of the genotype, patients with a shorter duration from onset of dystonia to surgery had better control of dystonia postoperatively. CONCLUSIONS: Long-term GPi-DBS is effective in patients with DYT6, DYT1, and non-DYT dystonia. However, the effect of DBS appears to be less predictable in patients with DYT6, suggesting that pre-DBS genetic testing and counseling for known dystonia gene mutations may be indicated. GPi-DBS should probably be considered earlier in the disease course. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial.

BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 µs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.

Asymmetric postural tremor preceding DOPA-responsive Parkinsonism - the transition disease.

BACKGROUND: Tremulous Parkinson's disease (PD) and essential tremor are well known to be associated, but characteristics of progression of pure tremor state to PD remain unclear. OBJECTIVE: In this prospective study a cohort of 16 patients suffering from a suggested new disease entity was clinically, pharmacologically, and sonographically analyzed to evaluate whether characteristics giving rise to a new entity in this field can be detected. METHODS: All patients had a history of asymmetric postural tremor (aPT) who either already had developed surplus Parkinsonism (PARK group), or were still in the state of a pure asymmetric postural tremor syndrome (APT group). Asymmetry of aPT was assessed by tremor scores including an asymmetry index. DOPA-responsivity was analyzed by tremor scores and the score of the motor part of the Unified Parkinson's disease rating scale. Transcranial brain sonography was performed to evaluate echogenicity of the substantia nigra. RESULTS: Mean age at onset of asymmetric postural tremor was 57 ± 8.5 years without significant differences between both groups. Family history was compatible with an autosomal-dominant inheritance pattern in the majority of patients of both the APT and PARK group. All patients in the PARK group and 3 out of 8 patients in the APT group (38%) with respect to their asymmetric postural tremor were DOPA-responsive. All patients of both groups eligible to transcranial brain sonography showed hyperechogenicity of substantia nigra. In both groups, there was no correlation between tremor severity and duration of asymmetric postural tremor. CONCLUSIONS: Our data indicate that patients with an initial asymmetric and sometimes DOPA-responsive postural tremor syndrome and PARK patients are at various stages within the transition from aPT to a later developed DOPA-responsive Parkinsonian syndrome. It is postulated that the described group of patients may represent a separate disease entity with a hereditary background.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial.

BACKGROUND: Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. METHODS: In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). FINDINGS: An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. FUNDING: Medtronic.

Value of combined midbrain sonography, olfactory and motor function assessment in the differential diagnosis of early Parkinson's disease.

OBJECTIVE: Characteristic features of Parkinson's disease (PD) are asymmetric parkinsonian motor signs, hyposmia and substantia nigra (SN) hyperechogenicity on transcranial ultrasound. However, each of these features has limited diagnostic value as they may be present, albeit less frequently, in other parkinsonian disorders. Here, the diagnostic sensitivity and specificity of combined assessment of these three features are evaluated. METHODS: 632 patients with parkinsonism (PD, vascular parkinsonism, atypical parkinsonian syndromes, essential tremor and major depressive disorder with motor slowing) were assessed on the Unified Parkinson's disease Rating Scale for motor asymmetry (right-left score difference ≥2), the 12 item Sniffin' Sticks test (SS-12) and transcranial ultrasound. The derivation (validation) cohort consisted of 517 (115) subjects (193 (35) women; age 65.4±9.6 (62.3±10.3) years) of whom 385 (68) had PD and 132 (47) non-PD parkinsonism; another 21 (6) subjects were not included due to missing transcranial insonability. Of the validation cohort, all patients had a disease duration ≤2 years and observers were blind to diagnoses. RESULTS: The optimum cut-off values for discrimination of PD were SS-12 score <8 (hyposmia) and SN echogenic size ≥0.24 cm(2) (SN hyperechogenicity). Sensitivity, specificity and positive predictive values for the diagnosis of PD were as follows, for the derivation cohort: motor asymmetry 88%, 54% and 85%; hyposmia 75%, 70% and 88%; SN hyperechogenicity 90%, 63% and 88%; two features present 96%, 72% and 91%; three features present 57%, 94% and 97%; and for the validation cohort: two features present 91%, 77% and 85%; three features present 49%, 98% and 97%. CONCLUSION: The combined assessment of motor asymmetry, hyposmia and SN hyperechogenicity improves diagnostic specificity and allows early diagnosis of PD.

Substantia nigra echogenicity in Parkinson's disease: relation to serum iron and C-reactive protein.

In Parkinson's disease (PD), substantia nigra hyperechogenicity (SN-h) has been related to both, local iron accumulation and microglia activation. We analysed its relationship in PD patients with serum iron (n = 31) and C-reactive protein (CRP; n = 193). SN-h correlated with lower CRP and iron levels. Also, patients with a first-degree relative with PD had lower iron levels. Microglia activation, if reflected by SN-h, may be therefore unrelated to serum CRP. Findings support the idea that SN-h indicates inherited alteration of iron metabolism.

Transcranial sonographic localization of deep brain stimulation electrodes is safe, reliable and predicts clinical outcome.

In patients with deep brain stimulation (DBS), poor postoperative outcome or unexpected clinical change require brain imaging to check the lead location. Here, we studied safety, reliability and prognostic value of transcranial sonography (TCS) for DBS lead localization applying predefined TCS criteria. After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected. Only patients with optimal lead position on TCS had favorable clinical 12-month outcome (>50% improvement), whereas unfavorable outcome (<25% improvement) was associated with suboptimal lead position. TCS may therefore become a first-choice modality to monitor lead location.

Mirror movements in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor syndrome with clinical evidence of upper and lower motor neuron dysfunction. Mirror movements (MM) in ALS have been reported and attributed to a disturbed transcallosal inhibition (TI). Hence, occurrence of MM in ALS might be explained by involvement of transcallosal projecting fibre tracts into the degenerative process of the motor system. Twenty-six consecutive ALS patients were studied by clinical investigation of MM and by transcranial magnetic stimulation testing of TI using evaluation of the ipsilateral silent period. MM were observed in 39% of ALS patients. There was a significant correlation between the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and occurrence of MM (correlation coefficient -0.315; p = 0.044). In conclusion, all MM patients had pathological TI at least in one hemisphere, which indicates involvement of transcallosally projecting output neurons in ALS patients, which in turn may be an early feature of the disease process with the potential of a diagnostic biomarker.

Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17.

Spinocerebellar ataxia (SCA17) is a rare genetic disorder characterized by a variety of neuropsychiatric symptoms. Recently, using magnetic resonance imaging (MRI) voxel-based morphometry (VBM), several specific functional-structural correlations comprising differential degeneration related to motor and psychiatric symptoms were reported in patients with SCA17. To investigate gray matter volume (GMV) changes over time and its association to clinical neuropsychiatric symptomatology, nine SCA17 mutation carriers and nine matched healthy individuals underwent a detailed neuropsychiatric clinical examination and a high-resolution T1-weighted volume MRI scan, both at baseline and follow-up after 18 months. Follow-up images revealed a progressive GMV reduction in specific degeneration patterns. In contrast to healthy controls, SCA17 patients showed a greater atrophy not only in cerebellar regions but also in cortical structures such as the limbic system (parahippocampus, cingulate) and parietal precuneus. Clinically, progression of motor symptoms was more pronounced than that of psychiatric symptoms. Correlation with the clinical motor scores revealed a progressive reduction of GMV in cerebellar and cerebral motor networks, whereas correlation with psychiatric scores displayed a more widespread GMV impairment in frontal, limbic, parietal, and also cerebellar structures. Interestingly, changes in global functioning were correlated with bilateral atrophy within the para-/hippocampus. While there was a good temporal association between worsening of motor symptoms and progression in cerebral and cortical neurodegeneration, the progression in psychiatric related neurodegeneration seemed to be more widespread and complex, showing progressive atrophy that preceded the further development of clinical psychiatric symptoms.

Altered callosal function in cerebral microangiopathy.

Callosal dysfunction is known to be evident in a variety of neurodegenerative and inflammatory diseases of the central nervous system. Cerebral microangiopathy (CMA) may also affect callosal pathways by chronic demyelination. The aim of the present study was to investigate callosal function with respect to the extent of CMA. Callosal function was tested by a bimanual tapping task and by analysis of the ipsilateral silent period (iSP) and the transcallosal conduction time (TCT) using transcranial magnetic stimulation. Results were correlated to the extent of CMA measured by cranial magnetic resonance imaging (cMRI) in 44 patients with CMA compared to 10 control subjects. The extent of CMA was quantified by a cMRI score. Additionally, callosal atrophy was quantified by cMRI morphometry. Frequency of pathological iSP findings or disturbed bimanual tapping was significantly correlated to a higher CMA score. Moreover, the extent of CMA was significantly correlated to the degree of callosal atrophy. It is concluded that CMA considerably affects callosal pathways, possibly by chronic demyelination of callosal fibres. As the extent of CMA and atrophy of the corpus callosum is correlated to callosal dysfunction, analysis of the iSP can be used to assess the clinical impact of CMA detected by cMRI.