Predictors of whole exome sequencing in dystonic cerebral palsy and cerebral palsy-like disorders.

INTRODUCTION: Cerebral palsy (CP) is a group of permanent disorders attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. Cerebral palsy-like (CP-like) disorders may clinically resemble CP but do not fulfill CP criteria and have often a progressive course and/or neurodevelopmental regression. To assess which patients with dystonic CP and dystonic CP-like disorder should undergo Whole Exome Sequencing (WES), we compared the rate of likely causative variants in individuals regarding their clinical picture, co-morbidities, and environmental risk factors. METHOD: Individuals with early onset neurodevelopmental disorder (ND) manifesting with dystonia as a core feature were divided into CP or CP-like cohorts based on their clinical picture and disease course. Detailed clinical picture, co-morbidities, and environmental risk factors including prematurity, asphyxia, SIRS, IRDS, and cerebral bleeding were evaluated. RESULTS: A total of 122 patients were included and divided into the CP group with 70 subjects (30 males; mean age 18y5m±16y6m, mean GMFCS score 3.3 ± 1.4), and the CP-like group with 52 subjects (29 males; mean age 17y7m±1y,6 m, mean GMFCS score 2,6 ± 1,5). The WES-based diagnosis was present in 19 (27.1%) CP patients and 30 CP-like patients (57.7%) with genetic conditions overlap in both groups. We found significant differences in diagnostic rate in CP individuals with vs. without risk factors (13.9% vs. 43.3%); Fisher's exact p = 0.0065. We did not observe the same tendency in CP-like (45.5% vs 58.5%); Fisher's exact p = 0.5. CONCLUSION: WES is a useful diagnostic method for patients with dystonic ND, regardless of their presentation as a CP or CP-like phenotype.

A case of novel DYT6 dystonia variant with serious complications after deep brain stimulation therapy: a case report.

BACKGROUND: DYT6 dystonia belongs to a group of isolated, genetically determined, generalized dystonia associated with mutations in the THAP1 gene. CASE PRESENTATION: We present the case of a young patient with DYT6 dystonia associated with a newly discovered c14G>A (p.Cys5Tyr) mutation in the THAP1 gene. We describe the clinical phenotype of this new mutation, effect of pallidal deep brain stimulation (DBS), which was accompanied by two rare postimplantation complications: an early intracerebral hemorrhage and delayed epileptic seizures. Among the published case reports of patients with DYT6 dystonia, the mentioned complications have not been described so far. CONCLUSIONS: DBS in the case of DYT6 dystonia is a challenge to thoroughly consider possible therapeutic benefits and potential risks associated with surgery. Genetic heterogeneity of the disease may also play an important role in predicting the development of the clinical phenotype as well as the effect of treatment including DBS. Therefore, it is beneficial to analyze the genetic and clinical relationships of DYT6 dystonia.

Atypical presentations of DYT1 dystonia with acute craniocervical onset.

DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.

Prevalence and evolution of spasticity in patients suffering from first-ever stroke with carotid origin: a prospective, longitudinal study.

BACKGROUND AND PURPOSE: The main aim of the study was to document the occurrence and evolution of post-stroke spasticity (PSS). The secondary goal was to identify predictors for increases and decreases in PSS rates during 12 months of subsequent follow-up. METHODS: In a longitudinal, multicenter, prospective cohort study, assessments were done at 7 days (V1), 6 months (V2), and 12 months (V3) after stroke onset. A total of 307 consecutive patients from four comprehensive stroke centers with the first-ever stroke of carotid origin and the presence of motor deficit at day 7 were included. The demographic data, baseline characteristics, Barthel index, degree and pattern of paresis and muscle tone were evaluated and recorded. Spasticity was assessed using the modified Ashworth scale. RESULTS: Spasticity was present in 45.0% of patients at V1, in 49.5% at V2, and in 43.2% at V3. A significant number of patients experienced changes in spasticity between visits: increased/new occurrence of spasticity in 32.5% (V1 and V2) and in 13.6% (V2 and V3) of patients; decreased occurrence/disappearance of spasticity in 18.5% (V1 and V2) and in 18.3% (V2 and V3) of patients. The number of patients with severe spasticity increased throughout the year, from 2.6% to 13.0% (V2) and 12.5% (V3). CONCLUSIONS: Spasticity developed in almost half of the included patients. The degree of spasticity often changed over time, in both directions. The rate of severe spasticity increased during the first year, with the maximum at 6 months following stroke onset.

GABA spectra and remote distractor effect in progressive supranuclear palsy: A pilot study.

Disturbances of the gamma-aminobutyric-acid (GABA) system have been suspected of contributing to the pathophysiology of progressive supranuclear palsy (PSP). The ability to rapidly resolve competitive action decisions, such as shifting the gaze to one particular stimulus rather than another, can be predicted by the concentration of GABA in the region of the frontal cortex relevant to eye movements. For this reason, our study measured GABA levels in seven PSP patients and eight healthy controls, using proton magnetic resonance spectroscopy, and assessed the relationship of these measurements to the remote distractor effect (RDE), an eye-movement paradigm investigating competitive action decisions. No significant differences were found in either frontal-eye-field GABA levels or RDE between PSP patients and controls.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Deep brain stimulation of the subthalamic nucleus and cognitive functions in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (DBS/STN) is an effective treatment for motor symptoms in advanced Parkinson's disease (PD). However, it is less clear how DBS/STN affects cognitive functions. We investigated 19 PD patients (13 male, 6 female, mean age 57 +/- 6, mean PD duration 15 +/- 4 years) who received bilateral DBS/STN. Neuropsychological assessment was done before the surgery and at least 12 months after DBS implantation. The patients were examined in their optimal motor status. Global cognitive performance measured by Mattis Dementia Rating Scale was not significantly changed after DBS STN. The performance in Wechsler Memory Scale III decreased in the subtest Logical Memory, in delayed recall (p < 0.05) and in recognition (p < 0.05). In Stroop Test, the performance worsened in the second (p < 0.05), and third condition (p < 0.01) measuring interference and ability to suppress automatic reactions. In conclusion, patients treated by DBS/STN tend to worsen in executive functions and in logical memory.

[Time perception in functional brain imaging]. / Vnímání casu ve funkcním zobrazení mozku.

BACKGROUND: Knowledge of physiological mechanisms underlying time perception is still rather limited. The aim of our study was to search for a 'time accumulator', i.e. the part of the brain where information on the duration of time is stored. METHODS AND RESULTS: Nine healthy volunteers were given a time reproduction task during event-related fMRI. Subjects were instructed to retain the duration of the stimulus presented (presentation phase) and then to reproduce it by pressing a button (reproduction phase). Two different analyses were made: event-related (P < 0.05, FWR corrected) and parametric (BOLD signal increase/decrease during the presentation/reproduction phases correlated with the time intervals; P < 0.01, FDR corrected). When the event-related approach was employed, activation was noted bilaterally in the inferior prefrontal cortex (IPFC), supplementary motor area (SMA), precuneus and secondary visual cortex. On the right, there was activation in the dorsolateral prefrontal cortex (DLPFC), gyrus cinguli and inferior parietal lobule. On the left, the primary sensory-motor cortex was activated. While during the presentation phase the left DLPFC activity inversely correlated with the presented duration, a nearly identical area showed positive correlation in the reproduction phase. CONCLUSIONS: The event-related analysis did not allow distinguishing the process of time perception from many cognitive processes running simultaneously. In turn, the parametric analysis was based on visualizing regions, in which the signal correlated with the varying duration of the time interval provided the level of attention, decision-making and the processes of behavioral response planning and execution were constant. Moreover, the right and left DLPFC seem to play different roles in time perception. While the left one is functioning as a "time accumulator", the right one is rather involved in the recognition of previously perceived intervals.

Rat spatial memory tasks adapted for humans: characterization in subjects with intact brain and subjects with selective medial temporal lobe thermal lesions.

In the present paper we describe five tests, 3 of which were designed to be similar to tasks used with rodents. Results obtained from control subjects, patients with selective thermo-coagulation lesions to the medial temporal lobe and results from non-human primates and rodents are discussed. The tests involve memory for spatial locations acquired by moving around in a room, memory for objects subjects interacted with, or memory for objects and their locations. Two of the spatial memory tasks were designed specifically as analogs of the Morris water task and the 8-arm radial-maze tasks used with rats. The Morris water task was modeled by hiding a sensor under the carpet of a room (Invisible Sensor Task). Subjects had to learn its location by using an array of visual cues available in the room. A path integration task was developed in order to study the non-visual acquisition of a cognitive representation of the spatial location of objects. In the non-visual spatial memory task, we blindfolded subjects and led them to a room where they had to find 3 objects and remember their locations. We designed an object location task by placing 4 objects in a room that subjects observed for later recall of their locations. A recognition task, and a novelty detection task were given subsequent to the recall task. An 8-arm radial-maze was recreated by placing stands at equal distance from each other around the room, and asking subjects to visit each stand once, from a central point. A non-spatial working memory task was designed to be the non-spatial equivalent of the radial maze. Search paths recorded on the first trial of the Invisible Sensor Task, when subjects search for the target by trial and error are reported. An analysis of the search paths revealed that patients with lesions to the right or left hippocampus or parahippocampal cortex employed the same type of search strategies as normal controls did, showing similarities and differences to the search behavior recorded in rats. Interestingly, patients with lesions that included the right parahippocampal cortex were impaired relative to patients with lesions to the right hippocampus that spared the parahippocampal cortex, when recall of the sensor was tested after a 30 min delay (Bohbot et al. 1998). No differences were obtained between control subjects and patients with selective thermal lesions to the medial temporal lobe, when tested on the radial-maze, the non-spatial analogue to the radial-maze and the path integration tasks. Differences in methodological procedures, learning strategies and lesion location could account for some of the discrepant results between humans and non-human species. Patients with lesions to the right hippocampus, irrespective of whether the right parahippocampal cortex was spared or damaged, had difficulties remembering the particular configuration and identity of objects in the novelty detection of the object location task. This supports the role of the human right hippocampus for spatial memory, in this case, involving memory for the location of elements in the room; learning known to require the hippocampus in the rat.

Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) was performed in patients with Parkinson's disease during deep brain stimulation of the subthalamic nucleus (three patients) and during deep brain stimulation of the ventral intermedius nucleus of the thalamus (one patient). All showed an increase in blood oxygenation level-dependent signal in the subcortical regions ipsilateral to the stimulated nucleus. This effect cannot be simply explained by a mechanism of depolarization blockade; rather, it is caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity. We confirm that fMRI during deep brain stimulation is a safe method with considerable potential for elucidating the functional connectivity of the stimulated nuclei.

Electromagnetic field of mobile phones affects visual event related potential in patients with narcolepsy.

The effects of the mobile phone (MP) electromagnetic fields on electroencephalography (EEG) and event-related potentials (ERP) were examined. With regard to the reported effects of MP on sleep, 22 patients with narcolepsy-cataplexy were exposed or sham exposed for 45 min to the MP (900 MHz, specific absorption rate 0.06 W/kg) placed close to the right ear in a double blind study. There were no changes of the EEG recorded after the MP exposure. A subgroup of 17 patients was studied on visual ERP recorded during the MP exposure. Using an adapted "odd-ball" paradigm, each patient was instructed to strike a key whenever rare target stimuli were presented. There were three variants of target stimuli (horizontal stripes in (i) left, (ii) right hemifields or (iii) whole field of the screen). The exposure enhanced the positivity of the ERP endogenous complex solely in response to target stimuli in the right hemifield of the screen (P < 0.01). The reaction time was shortened by 20 ms in response to all target stimuli (P < 0.05). In conclusion, the electromagnetic field of MP may suppress the excessive sleepiness and improve performance while solving a monotonous cognitive task requiring sustained attention and vigilance.

Investigation of non-linear properties of multichannel EEG in the early stages of Parkinson's disease.

OBJECTIVES: Modifications of brain activity in the early stages of Parkinson's disease (PD) are difficult to detect using electroencephalography (EEG) signals and are often biased by L-DOPA treatment. We compare here the performances of both linear and non-linear methods in differentiating EEG of L-DOPA naive PD patients from that of control subjects. METHODS: Resting multichannel EEG (20 electrodes, 30 s epochs) of 9 patients with PD in Hoehn and Yahr stages 1-2 (4 women, 5 men, mean age 54.3 years, range 48-63 years) were compared with those of 9 control subjects (7 women, two men, mean age 51.3 years, range 43-61 years). The following measurements were computed: theta-, alpha- and beta-band relative powers constituted the linear indices; localized entropy, slope asymmetry and number of non-linear EEG segments constituted the non-linear indices. RESULTS: In the case of linear quantification, only a decrease in the beta-band was observed for patients. Significant non-linear structures were observed in our EEG data. Non-linear quantifiers demonstrate an increase in entropy and in the number of non-linear EEG segments for the patients. CONCLUSIONS: Changes in EEG dynamics observed here in L-DOPA naive PD patients may represent early signs of cortical dysfunction produced by subcortical dopamine depletion.

Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study.

Results from a dose-ranging study in a selected group of de novo patients with rotational cervical dystonia (CD) suggest that 500 units of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) is the optimal starting dose. The present study aimed to confirm the efficacy and safety profile of this dose in a population of CD patients more representative of those seen in a typical dystonia clinic. A total of 68 patients with moderate to severe CD (Tsui score > or = 9) were randomly assigned to receive placebo or Dysport 500 units. Treatment was administered according to the clinical pattern of head deviation, using a standardised injection protocol. A total of 21 patients (11 Dysport, 10 placebo) had not previously received botulinum toxin type A (BtxA) injections, and 47 patients (24 Dysport, 23 placebo) had received BtxA more than 12 weeks previously. Assessments were performed at baseline and weeks 4, 8 and 16. Patients defined as non-responders at week 4 were re-treated in an open phase with 500 units of Dysport at week 6, and were followed up at week 10. Significant between-group differences in Tsui scores were present at weeks 4 (p=0.001) and 8 (p=0.002). Similarly, there were significant between-group differences (p < 0.001) in patient and investigator assessments of response in favour of Dysport at weeks 4 and 8. Also, more Dysport (49%) than placebo (33%) patients were pain-free at week 4 (p=0.02). Overall, 30/35 (86 %) Dysport patients and 14/33 (42%) placebo patients were classified as responders at week 4. Adverse events were reported by 15/35 Dysport patients and 9/33 placebo patients. Open phase treatment produced improvements in Tsui (p < 0.001) and pain scores (p=0.011), and 23/24 patients were classified as responders. Although individual dose titration and muscle selection is desirable, this study demonstrated that a dose of 500 units of Dysport injected into clinically identified neck muscles without electromyographic guidance is safe and effective in the treatment of patients with the major clinical types of cervical dystonia.

Colour discrimination impairment is not a reliable early marker of Parkinson's disease.

Disturbances of colour visual discrimination have been shown to occur frequently in Parkinson's disease (PD). To verify the potential utility of reduced colour sensitivity as a diagnostic marker of early PD, we examined 14 PD patients, mean age 55.4 years, disease duration 2.3 years, in Hoehn and Yahr stages 1, 1.5, or 2, previously untreated with levodopa. Colour discrimination was measured with the Farnsworth-Munsell 100-hue test in patients who were compared with age-matched controls. The examinations were performed under standard conditions in a room illuminated by a daylight lamp Biolux Osram 6500 K. The mean total error score (MTES) and partial error scores (green-yellow and red-green axis) were calculated for every person examined. No significant differences were found between PD patients (MTES 49.1 +/- SD 37) and controls (MTES 37.9 +/- SD 25). Similarly, the mean partial scores were not significantly elevated in PD patients. We found an elevation of error scores exceeding the upper limit of normality (control mean + 2SD) only in three patients. We conclude that colour visual discrimination is not consistently impaired in early stages of PD and does not appear as a reliable early marker of Parkinson's disease.

Amantadine infusion in treatment of motor fluctuations and dyskinesias in Parkinson's disease.

Efficiency and safety of amantadine sulfate (AMS) infusions were investigated in late stage complications of Parkinson's disease (PD). In an open-label study, 21 PD patients suffering from motor fluctuations and/or dyskinesias were administered AMS infusions (PK-Merz, 400 mg per day) during seven days. Oral AMS treatment followed. Significant improvement of UPDRS motor scores was observed between day 0 and day 7, remaining improved until day 21. Based on patients' diary notes, both severity and occurrence of hypokinetic "off" state significantly decreased (from 6.6 to 3.1 hours, p < 0.001, average "off" time per day) as well as dopaminergic-induced dyskinesias (from 2.5 to 1.3 hours, p < 0.05, average duration of dyskinesias per day). AMS infusions followed by oral administration appeared as a safe method for improvement of both motor fluctuations and dyskinesias in advanced PD. In advantage to simple oral therapy, AMS infusions allowed fast introduction of a profound and durable treatment effect.

Huntington's disease: the relationship between clinical signs, CAG repeats and the atrophy of the caudate nucleus in CT scans.

We compared clinical data from 45 patients with Huntington's Disease (HD) with CAG triplet repeats and the planimetric measurement of the caudate nucleus head area (CNHA) in CT scans. The mean age of patients was 50.4 yrs (SD +/- 10.2), the mean duration of HD 7.4 yrs (4.6), the mean age at the onset of HD 43.1 yrs (11.1). HD started with motor symptoms in 28 patients, with psychiatric symptoms in 14 patients, the history was unknown in 3 patients. The paternal transmission was observed in 29 patients, the maternal one in 12 patients, unknown in 4 patients. The mean number of CAG repeats was 46.6 (6.1). The mean CNHA was 0.4 cm2 (0.1). We found statistically significant reversed correlation between CAG repeats and the age at the onset of HD (p < 0.0001, r -0.6). The earlier onset of HD in patients with the paternal transmission compared to the maternal one was found statistically significant (p < 0.05). This phenomenon was not related to the larger number of CAG triplets in patients with the paternal transmission. No differences either of the age at the onset of HD or numbers of CAG repeats were found between subgroups of HD patients starting with motor or psychiatric symptoms. We also observed the significant reversed correlation between the duration of HD and CNHA measurement (p < 0.001, r -0.5). Even in the earliest stage of HD patients showed the marked atrophy of CNHA.

Apomorphine does not influence olfactory thresholds in Parkinson's disease.

In order to verify the presumed dopaminergic basis of olfactory dysfunction in Parkinson's disease (PD), we studied olfactory functions in 12 PD patients (mean age 60.1 yrs, mean duration of PD 9.0 yrs, mean Hoehn and Yahr score 2.8) before and after apomorphine (APO) administration. Amylacetate (banana smell) in 12 sequential dilutions (in 50% steps) was used for the examination of olfactory thresholds. The testing showed no significant differences in any olfactory parameters before and after APO. Furthermore, when analysing the subgroup of 7 hyposmic PD patients, we also found no significant differences before and after APO. We therefore believe that olfactory dysfunction in PD is not dependent on dopamine deficiency.

[Residual findings in retrobulbar neuritis during demyelinization]. / Reziduální nálezy u retrobulbárních neuritid pri demyelinizaci.

Retrobulbar neuritis is a common clinical manifestation of multiple sclerosis. We evaluated and compared the results of visual field and fundus examinations, visual evoked response and nuclear magnetic resonance of the brain in 37 patients with the diagnosis of multiple sclerosis and retrobulbar neuritis. Diffuse, peripheral scotomas seemed to be the most often found scotomas on perimetry in these patients. In contrary, central scotomas formed just a little part of the visual field defects. Each threshold increasing of 0.10 log. units on perimetry was followed by increased latencies of 2.5 ms. Each other central scotoma on perimetry decreased the visual acuity of the patient for 1.6 lines on the Snellen chart. The central visual field examination without periphery in the patients with multiple sclerosis and retrobulbar neuritis seems to give false negative results.