Delirium on stroke units: a prospective, multicentric quality-improvement project.

BACKGROUND: Post-stroke delirium (POD) in patients on stroke units (SU) is associated with an increased risk for complications and poorer clinical outcome. The objective was to reduce the severity of POD by implementing an interprofessional delirium-management. METHODS: Multicentric quality-improvement project on five SU implementing a delirium-management with pre/post-comparison. Primary outcome was severity of POD, assessed with the Nursing Delirium Screening Scale (Nu-DESC). Secondary outcome parameters were POD incidence, duration, modified Rankin Scale (mRS), length of stay in SU and hospital, mortality, and others. RESULTS: Out of a total of 799 patients, 59.4% (n = 475) could be included with 9.5% (n = 45) being delirious. Implementation of a delirium-management led to reduced POD severity; Nu-DESC median: pre: 3.5 (interquartile range 2.6-4.7) vs. post 3.0 (2.2-4.0), albeit not significant (p = 0.154). Other outcome parameters were not meaningful different. In the post-period, delirium-management could be delivered to 75% (n = 18) of delirious patients, and only 24 (53.3%) of delirious patients required pharmacological treatments. Patients with a more severe stroke and POD remained on their disability levels, compared to similar affected, non-delirious patients who improved. CONCLUSIONS: Implementation of delirium-management on SU is feasible and can be delivered to most patients, but with limited effects. Nursing interventions as first choice could be delivered to the majority of patients, and only the half required pharmacological treatments. Delirium-management may lead to reduced severity of POD but had only partial effects on duration of POD or length of stay. POD hampers rehabilitation, especially in patients with more severe stroke. REGISTRY: DRKS, DRKS00021436. Registered 04/17/2020, www.drks.de/DRKS00021436 .

Functional impact of different muscle localization techniques for Botulinum neurotoxin A injections in clinical routine management of post-stroke spasticity.

BACKGROUND: Treatment options for spasticity include intramuscular botulinum neurotoxin A (BoNT-A) injections. Both ultrasound (US) or electromyographic (EMG) guided BoNT-A injections are employed to isolate muscles. To date, most studies have included patients naïve to BoNT-A or following a prolonged wash out phase. OBJECTIVE: To determine the impact of US/EMG guided BoNT-A injections on function in outpatients with spasticity receiving an established re-injection regime. METHODS: Thirty patients post-stroke were investigated in a single-blinded, randomized controlled trial using a cross-over design for the EMG and US and a parallel design for the control group. The Modified Ashworth (MAS), Disability Assessment (DAS), Quality of Life (EQ-5D), self-rating scale and Barthel Index were assessed pre- and post-BoNT-A injections of upper limb muscles by a to the injection technique blinded person. RESULTS: MAS improved in arm, finger and upper limb 4 weeks after BoNT-A treatment. The improvement showed no significant differences between the three injection techniques. Barthel Index, DAS and EQ-5D remained unchanged in all groups. CONCLUSIONS: This pilot study questions the impact of the instrumental guided injection techniques on everyday functionality in a routine clinical setting with established re-injection intervals. Larger trials are warranted with patients who are under long-term treatment on a regular basis.

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.

A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes.

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50-60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.

Modulation of gait coordination by subthalamic stimulation improves freezing of gait.

The effect of subthalamic deep brain stimulation on gait coordination and freezing of gait in patients with Parkinson's disease is incompletely understood. The purpose of this study was to investigate the extent to which modulation of symmetry and coordination between legs by subthalamic deep brain stimulation alters the frequency and duration of freezing of gait in patients with Parkinson's disease. We recruited 13 post-subthalamic deep brain stimulation patients with Parkinson's disease with off freezing of gait and evaluated them in the following 4 conditions: subthalamic deep brain stimulation on (ON) and stimulation off (OFF), 50% reduction of stimulation voltage for the leg with shorter step length (worse side reduction) and for the leg with longer step length (better side reduction). Gait analysis was performed on a treadmill and recorded by an optoelectronic analysis system. We measured frequency and duration of freezing of gait episodes. Bilateral coordination of gait was assessed by the Phase Coordination Index, quantifying the ability to generate antiphase stepping. From the OFF to the ON state, freezing of gait improved in frequency (2.0 ± 0.4 to 1.4 ± 0.5 episodes) and duration (12.2 ± 2.6 to 2.6 ± 0.8 seconds; P = .005). Compared with the ON state, only better side reduction further reduced freezing of gait frequency (0.2 ± 0.2) and duration of episodes (0.2 ± 0.2 seconds; P = .03); worse side reduction did not change frequency (1.3 ± 0.4) but increased freezing of gait duration (5.2 ± 2.1 seconds). The better side reduction-associated improvements were accompanied by normalization of gait coordination, as measured by phase coordination index (16.5% ± 6.0%), which was significantly lower than in the other 3 conditions. Reduction of stimulation voltage in the side contralateral to the leg with longer step length improves frequency and duration of freezing of gait through normalization of gait symmetry and coordination in subthalamic deep brain stimulation patients with Parkinson's disease. This identifies poor leg coordination as a risk factor for causing freezing of gait.

Cortical representation of rhythmic foot movements.

The cortex is involved in rhythmic hand movements. The cortical contribution to rhythmic motor patterns of the feet, however, has never been evaluated in humans. In this study we investigated EEG activity related to rhythmic stepping and tapping movements in 10 healthy subjects. Subjects performed self-paced fast bilateral anti-phase, in-phase and unilateral rhythmic foot movements as well as an isometric cocontraction of the calf muscles, while being seated as relaxed as possible. Surface EMG from the anterior tibial muscles was recorded in parallel with a 64 channel EEG. Power spectra, corticomuscular coherence and corticomuscular delay were calculated. All subjects showed corticomuscular coherence at the stepping frequencies in the central midline region that extended further to the frontal mesial area. The magnitude and the topography of this coherence were equal for the right and left anterior tibial muscle and all movement conditions. During cocontraction there was coherence in the 15-30 Hz range which was refined to the central midline area. EEG-EMG delays were significant in 9 subjects with values between 14 and 26 ms, EMG-EEG feedback was only found in 6 subjects with delays between 25 and 40 ms. We conclude that rhythmic motor patterns of the feet are represented in the cortex, transmitted to the muscles with delays compatible with fast corticospinal transmission and fed back to the cortex. A similar cortical contribution may be important also for gait control in humans.

REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia--report of 19 cases.

Hereditary spastic paraplegia (HSP) is characterized by lower extremity spasticity. Symptomatic therapy generally includes physical therapy and oral antispastic agents, in selected cases intrathecal baclofen. Because of the positive results in other treatments of spasticity, the use of botulinum neurotoxin type A (BoNT-A) might also be considered for patients with HSP. We report the effect of BoNT-A injections in 19 unselected patients with HSP treated by the members of the German Spasticity Education Group. In 17 patients, the modified Ashworth scale had improved by one point. In one patient, it improved by three points. Most of the patients reported reduction of spasticity. BoNT-A injections were continued in 11 of 19 patients (57.9%). All of the patients with continued injections had a good or very good global subjective improvement. Patients with less pronounced spasticity and patients with accompanying physical therapy tended to exhibit a better effect. Only four patients reported adverse effects which were increased weakness in three patients and pain in one patient. BoNT-A injections appear to reduce spasticity effectively and safely, especially in patients with mild to moderate spasticity. The preliminary results of our case series should encourage larger studies of BoNT-A injections in HSP.

Methylphenidate fails to improve gait and muscle tone in patients with sporadic and hereditary spastic paraplegia.

Based on its action on multiple neurotransmitters, including dopamine, methylphenidate (MPH) is of growing interest as a possible treatment option for several movement disorders. Of special interest are diseases that share gait disturbance and cognitive decline. Based on a single case observation in a patient with hereditary spastic spinal paraplegia (HSP) in which gait was improved with MPH, we performed an open-label study with a longitudinal follow-up in 22 patients with HSP and its sporadic form (SSP). The patients were treated for 6 months with 60 mg of MPH per day. Computerized gait analysis and different scores were performed at baseline, after 6 weeks, and after 6 months of treatment. Although at 6 weeks, the gait velocity was somewhat improved, the drug failed to show any effect on other gait parameters and had no beneficial effect at all after 6 months. Although MPH is of interest for several movement disorders, our study did not show a beneficial effect.

Hand coordination following capsular stroke.

Motor outcome following stroke of the internal capsule is variable and its determinants are poorly understood. While many patients fully regain their abilities, recovery of motor functions remains incomplete in others. We analysed functional motor tasks of the upper limb to determine the pattern of focal disability after a small infarct of the internal capsule ('pure motor stroke') in the chronic stage (mean 2.4 years after stroke) with kinematic recordings of a reaching-to-grasp movement, with a quantitative analysis of the precision grip, and with clinical rating scales. The location of the lesions within the posterior limb of the internal capsule (PLIC) in 18 patients was determined from neuroimages obtained in the acute stage (5-20 days after the insult). Involvement of the PLIC was assessed at the level of the basal ganglia, approximately 8 mm above the anterior commissure-posterior commissure level. The distance between the posterior edge of the internal capsule and the centre of gravity of the lesion was determined. Chronic disabilities affected dextrous movements, while paresis was mild and sensitivity for light touch or passive finger flexion was almost normal. For both the reaching-to-grasp movement and the precision grip paradigm, the slowness of movement or force development was confined to the phases when grip formation and stabilization occur, while the onset of hand transport and of the vertical lifting force were not delayed. Grip forces were increased. We observed a close correlation between posterior location within the PLIC and the altered measures of timing and precision grip force. The more posterior the acute lesion was located within the PLIC, the more pronounced were the chronic motor deficits, as seen both in the quantitative measures and in the rating scales. The present study demonstrates for the first time that the amount and quality of chronic motor deficits of dextrous movements are related to a simple measure drawn from routine neuroimaging in the acute stage in patients with capsular stroke. The poor motor outcome in lesions involving the most posterior parts of the PLIC could be due to the condensed organization of corticofugal projections and the density of pyramidal fibres from the primary motor cortex in this subsector. Even small infarcts of this strategic area can disrupt many of the projections from the motor cortices and could thereby limit recovery strategies between homolateral motor representations.

Prevalence of gait disorders in hospitalized neurological patients.

The prevalence of gait disorders among neurological inpatients is unknown, although disturbed gait is a common symptom. Gait disorders often lead to loss of independence with restraints for the patients and caregivers and costs for the health system. We designed a prospective study and investigated all patients admitted to a neurological hospital during a 100-day period for the presence of a gait disorder. Clinical investigation and several disease-specific rating scales were carried out for 493 patients. In 60% of the patients, a disturbance of gait was diagnosed. Most frequent diagnoses were stroke (21%), Parkinson's disease (17%), and polyneuropathy (7%). Within these diagnoses, the rate of patients with disturbed gait was high in Parkinson's disease (93%), subcortical arteriosclerotic encephalopathy (85%), and motor neuron disease (83%). Advanced age, dementia, alcohol abuse, and treatment with antiepileptics, neuroleptics, benzodiazepines, and chemotherapeutics were identified as risk factors for a gait disorder. A decline of cognitive function was accompanied by a reduction of walking speed. According to these results, gait disorders are among the most frequent symptoms in neurology.

Is the rhythm of physiological tremor involved in cortico-cortical interactions?

The function of low-frequency oscillations as correlates of physiological tremor in supplementary motor area (SMA) and M1 remains unclear. In epicortical recordings from M1 and SMA and surface electromyographic (EMG) recordings in an epileptic patient we found reproducibly significant coherence between all three recording sites in the 6- to 15-Hz band. The partial coherence between SMA and muscle, however, was not significant. There was a constant phase shift between SMA and M1 indicating synchronized activity. We conclude that the cortical correlates of physiological tremor may be involved in linking different cortical motor centers and might therefore play a role in cortical motor planning.

Falls in frequent neurological diseases--prevalence, risk factors and aetiology.

The prevalence of falls among neurological patients is unknown, although disturbances of gait and posture are common. Falls may lead to burdens for the patient, the caregivers and the health system. We designed a prospective study and investigated all patients for a history of falls admitted to a neurological hospital during a 100-day period. Clinical investigation was carried out and several disease specific rating scales were applied. A total of 548 patients were investigated. Of all patients 34% had fallen once or more often during the last twelve months. A disturbance of gait was blamed for the fall in 55%, epileptic seizures in 12%, syncope in 10 % and stroke in 7%. Intrinsic risk factors for falls were high age, disturbed gait, poor balance and a fear of falling. As extrinsic factors we identified the treatment with antidepressants, neuroleptics and different cardiovascular medications, adverse environmental factors in the patients' home and the use of walking aids. Within the diagnoses, falls were most frequent in Parkinson's disease (62 %), syncope (57%) and polyneuropathy (48 %). According to these findings falls in neurological in-patients are twice as frequent as in an age-matched population living in the community. Falls in neurological patients are particularly linked to medication and disorders affecting gait and balance.

Analyses of gait, reaching, and grasping in children after traumatic brain injury.

OBJECTIVE: To evaluate motor behavior in children after traumatic brain injury (TBI) with quantitative instrumented measures of gait and of functional hand movements (reaching, grasping) and with clinical assessments. DESIGN: Case-control study. SETTING: Tertiary pediatric trauma rehabilitation center in Germany. PARTICIPANTS: Twenty children (age range, 6-13 y) with moderate or severe TBI were examined 1+/-1.2 years (mean +/- standard deviation) postinjury. Fifteen were reexamined 2 months later. Control data were obtained from 20 healthy children and matched for age, gender, and school grade. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Quantitative measures included 10 spatiotemporal gait parameters and 6 variables describing reaching and grasping. Qualitative scores of gait and upper-limb movements were also obtained. RESULTS: Gait velocity and step and stride lengths were significantly smaller in children after TBI than in control subjects (Mann-Whitney U test, P<.05). Reach-to-grasp movements of the TBI children were characterized by a significantly longer reaction time (Mann-Whitney U test, P<.05) and movement duration, reduced velocity, and coordination deficits. The instrumented measures did not change significantly in 2 months. Several significant correlations between clinical and instrumented measures were obtained. CONCLUSION: Functional motor behavior is affected in children after moderate or severe TBI. To supplement clinical assessments with objective data, impairments of gait, reaching, and grasping movements can be recorded with instrumented measures.

Corticomuscular coherence in the 6-15 Hz band: is the cortex involved in the generation of physiologic tremor?

Physiologic tremor (PT) consists of a peripheral mechanical oscillation at the limbs' resonance frequency and an independent central component in the 6-15 Hz band. This central component has mainly been attributed to spinal interneuronal systems or subcortical oscillators but more recently also to cortical rhythms. We recorded PT electromyographically and accelerometrically from different parts of the arm in parallel to epicortical recordings from grid electrodes covering the primary sensorimotor areas of the contralateral cortex in six epileptic patients. Previous bipolar electrical stimulation of the cortical electrodes resulted in a somatotopic map of the primary cortex underlying the grid. Spectral and cross-spectral analysis including coherence spectra between epicortical electrodes and EMG and the corresponding phase spectra were performed off-line. We found significant corticomuscular coherence in the 6-15 Hz range in four out of the six patients. This coherence was focal on the cortex and it was distributed somatotopically mainly within the primary motor area. The frequency band of the coherence mostly corresponding to the EMG frequency remained stable with added inertia, while the main accelerometric frequency was clearly reduced following the resonance frequency. The phase spectra between electrocorticogram (ECoG) and EMG showed a clear delay between cortex and muscle in two of the patients, which was compatible with conduction in fast pyramidal pathways. These findings indicate that the 6-15 Hz coherence between cortex and EMG reflects a corticomuscular transmission of the oscillation rather than peripheral feedback to the cortex. We conclude that cortical networks are involved in the generation of physiologic tremor.

Assessment of sensorimotor functions after traumatic brain injury (TBI) in childhood - Methodological aspects.

Various basic qualitative and quantitative methods for the evaluation of sensorimotor functions after Traumatic Brain Injury (TBI) are introduced and discussed. Methodological aspects are illustrated by a single case follow-up study of a child after severe TBI (age 11; 7-12;1 yrs; 6, 8 and 12 month post TBI) in comparison to an age-matched healthy control group (N=16). The evaluation consisted of neurological investigation, Barthel-Index, Terver Numeric Score for Functional Assessment, Rappaport Disability Rating Scale (modified version), a coordination-test for children (KTK), a pilot-tested Motor Function Score, quantitative evaluation of spatiotemporal gait parameters on a walkway and on a treadmill, and the kinematic assessment of hand motor functions. Quantitative movement analyses revealed two general types of motor disorder: Slowing of movements and compensatory motor strategies. Averaged z-scores showed deficits, which were pronounced in fine motor skills (hand movements: 1.86, gait: 1.3). During follow-up, a strong improvement rate during the first (-0.48 z-scores) and nearly no improvement rate (-0.03 z-scores) during the second time interval was seen. Clinical scores and developmental tests were not able to document the whole restitutional course, whereas motor tests with special emphasis on functional aspects and the quantitative movement assessment seemed to be suitable methods. We conclude that a sufficient evaluation of sensorimotor functions after TBI in childhood needs an increase in procedural uniformity on onehand and the combination of various qualitative and quantitative methods on the other hand. To connect both claims, further research is necessary.