Post-Stroke Spastic Movement Disorder and Botulinum Toxin A Therapy: Early Detection And Early Injection.

Post-stroke spastic movement disorder (PS-SMD) develops in up to 40% of stroke survivors after a first ever stroke within the first year. Chronic PS-SMD is often associated with severe disabilities and complications, emphasizing the importance of its early recognition and early adequate management. Extensive research has aimed to accurately predict and sensitively detect a PS-SMD. Symptomatic therapies include conventional rehabilitation and local intramuscular injections of botulinum toxin A (BoNT-A). The latter is widely used, but primarily in the chronic phase of stroke. However, recent studies have shown the safety and efficacy of BoNT-A therapy even in the acute phase and early sub-acute phase after stroke, i.e., within three months post-stroke, leading to an improved long-term outcome in stroke rehabilitation. Local BoNT-A injections evolve as the primary approach in focal, multifocal, and segmental chronic or acute/subacute PS-SMD. Patients at high risk for or manifest PS-SMD should be identified by an early spasticity risk assessment. By doing so, PS-SMD can be integral part of the patient-centered goal-setting process of a multiprofessional spasticity-experienced team. The benefit of an early PS-SMD treatment by BoNT-A should predominate putative degenerative muscle changes due to long-term BoNT-A therapy by far. This, as early treatment effectively avoids complications typically associated with a PS-SMD, i.e., contractures, pain, skin lesions. The management of PS-SMD requires a comprehensive and multidisciplinary approach. Early assessment, patient-centered goal setting, early intervention, and early use of BoNT-A therapy prevents from PS-SMD complications and may improve rehabilitation outcome after stroke.

Early versus late injections of Botulinumtoxin type A in post-stroke spastic movement disorder: A literature review.

Post-stroke spastic movement disorder (PS-SMD) is one of the main causes of severe disability in the chronic phase after stroke. The prevalence of SMD goes up with time after stroke to more than 28% in the chronic phase., Its secondary complications such as contracture, abnormal postures and/or movement patterns, spasticity-associated pain also increase with time after stroke when physical and medical management of PS-SMD have been delayed in the early stroke phase. It has been published by several controlled studies that the earlier physical and medical measures, such as botulinum toxin type A (BoNT-A) therapy are included in rehabilitative strategies for the SMD, the fewer secondary complications, especially soft tissue contractures and pain occurred. Several studies showed that goal-orientated management of PS-SMD including BoNT-A therapy, applied within a few weeks and three months - in the early subacute phase after stroke onset - prevented or reduced the development of severe or disabling SMD and its secondary complications, more effective than late application of BoNT-A therapy - in the chronic phase after stroke. In multiple prospective cohort studies, various predictors and predictive approaches for detection of patients on risk to development PS-SMD were found. Based on that information and the controlled studies that showed reduction in PS-SMD complications following early treatment with BoNT-A nowadays, early treatment of PS-SMD in the early subacute phase following stroke is recommended to avoid or reduce the development of post-stroke disability and to improve the outcome of rehabilitation. In this review, we discuss the optimal timing to apply BoNT-A therapy in patients with already present as well as those at high risk of severe PS-SMD.

The Safety and Effect of Local Botulinumtoxin A Injections for Long-Term Management of Chronic Pain in Post-Herpetic Neuralgia: Literature Review and Cases Report Treated with Incobotulinumtoxin A.

There are few reports on the safety and effectiveness of long-term botulinumtoxin A (BoNT A) therapy in severe chronic pain of post-herpetic neuralgia (PHN). The literature was searched with the term "neuropathic pain" and "botulinum" on PubMed (up to 29 February 2020). Pain was assessed with the Visual Analogue Scale (VAS) before and after BoNT A therapy. A total of 10 clinical trials and six case reports including 251 patients with PHN were presented. They showed that BoNT A therapy had significant pain reduction (up to 30-50%) and improvement in quality of life. The effect duration seems to be correlated with BoNT A doses injected per injection site. Intervals between BoNT A injections were 10-14 weeks. No adverse events were reported in cases and clinical studies, even in the two pregnant women, whose babies were healthy. The repeated (≥6 times) intra/subcutaneous injections of incobotulinumtoxin A (Xeomin®, Merz Pharmaceuticals, Germany) over the two years of our three cases showed marked pain reduction and no adverse events. Adjunctive local BoNT A injection is a promising option for severe PHN, as a safe and effective therapy in long-term management for chronic neuropathic pain. Its effect size and -duration seem to be depended on the dose of BoNT A injected per each point.

What clinicians and patients want: The past, the presence, and the future of the botulinum toxins.

Botulinum toxin (BoNT) is well established in clinical practice for more than 30 years. During this time the area of applications was broaden beyond the ophtalmologic and neurologic indications. Despite of decades of BoNT application with a huge increase of expertise and supporting methods for utilization as well, both patients and physicians claim about boundaries and limits in their daily treatment practice. Most of those limits are related to the toxin itself and its pharmacokinetic properties. The challenge in the field of movement disorders, swetting, and sialorrhea to combine all fast onset, long-lasting effect, safe application free of pain, and the possibility to vary therapy strategies in dosage and application intervals is pervasive and recurrent. In the present article we attempt to name challenges, patient's and physician's wishes. On the base of the toxins that we have and that we are going to get we imagine optimized therapy settings for the core neurological indications spastic movement disorder, dystonia, swetting, and sialorrhea.

Site and size of lesion predict post-stroke spasticity: A retrospective magnetic resonance imaging study.

OBJECTIVE: Clinical parameters for prediction of post-stroke spasticity are well established. This report introduces 2 brain magnetic resonance imaging (MRI) parameters (infarct volume and topographic distribution) as post-stroke spasticity predictors. METHODS: Topographic and volumetric data from brain MRI for 98 patients with ischaemic stroke with spasticity, prevalent within the first 5 days after stroke and 6 months after stroke, were retrospectively correlated using Chris Rorden's MRIcron software. RESULTS: Lesions within the supply territory of the middle cerebral artery involving the pyramidal tract were more frequently associated with spasticity than without spasticity (30.8% vs 5.1%). Middle cerebral artery lesions not affecting the pyramidal tract were found more often in patients without spasticity (49.2% vs 10.3%). Spasticity showed a significantly higher association with middle cerebral artery+pyramidal tract/internal capsule lesions than did "no spasticity" (97.5% vs 18.7%, p < 0.01), and lesion volumes were significantly larger in patients with spasticity than in those without spasticity (p < 0.01). CONCLUSION: Large stroke volumes might predict post-stroke spasticity if the lesion is > 3 cm3 in size and if the lesion is located within the middle cerebral artery territory with involvement of the pyramidal tract and/or internal capsule. Lesion size ≤ 2 cm3 outside the middle cerebral artery territory is associated with lower risk of post-stroke spasticity.

Postoperative MRI localisation of electrodes and clinical efficacy of pallidal deep brain stimulation in cervical dystonia.

INTRODUCTION: Pallidal deep brain stimulation (DBS) has been shown to be effective in cervical dystonia (CD) with an improvement of about 50-60% in the Toronto Western Spasmodic Torticollis Rating (TWSTR) Scale. However, predictive factors for the efficacy of DBS in CD are missing with the anatomical location of the electrodes being one of the most important potential predictive factors. METHODS: In the present blinded observational study we correlated the anatomical localisation of DBS contacts with the relative clinical improvement (CI %) in the TWSTR as achieved by DBS at different pallidal contacts in 20 patients with CD. Localisations of DBS contacts were derived from postoperative MRI-data following anatomical normalisation into the standard Montreal Neurological Institute stereotactic space. The CIs following 76 bilateral test stimulations of 24 h were mapped to stereotactic coordinates of the corresponding bilateral 152 active contacts and were allocated to low CI (<30%; n=74), intermediate CI (≥30%; <60%; n=52) or high CI (≥60%; n=26). RESULTS: Euclidean distances between contacts and the centroid differed between the three clusters (p<0.001) indicating different anatomical variances between clusters. The Euclidean distances between contacts and the centroid of the cluster with high CIs correlated with the individual level of CIs (r=-0.61; p<0.0001). This relationship was best fitted with an exponential regression curve (r(2)=0.41). DISCUSSION: Our data show that the clinical effect of pallidal DBS on CD displays an exponential decay over anatomical distance from an optimised target localisation within a subregion of the internal pallidum. The results will allow a comparison of future DBS studies with postoperative MRI by verifying optimised (for instance pallidal) targeting in DBS-treated patients.

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.

Stenosis or hyperperfusion in sickle cell disease--ultrasound assessment of cerebral blood flow volume.

Increased blood flow velocity (BFV) in basal cerebral arteries measured by transcranial color-coded sonography (TCCS) is a stroke risk factor in sickle cell disease (SCD). Raised BFV may be caused by vessel narrowing or by hyperperfusion. In 44 SCD patients and 14 controls, intracranial arterial BFVs and global cerebral blood flow (CBF) were analyzed by TCCS and extracranial duplex ultrasound, respectively. Magnetic resonance imaging and magnetic resonance angiography were performed in all patients with pathologic intracranial BFV rise. Intracranial BFVs and CBF in SCD were significantly higher than in controls. CBF in SCD correlated with BFV in all intracranial arteries and correlated inversely with age and hemoglobin values. Magnetic resonance angiography failed to demonstrate any stenosis in our SCD patients, thus raised intracranial BFVs must be interpreted as an anemia-dependent cerebral hyperperfusion. These findings suggest that the pathomechanism of stenosis-derived arterio-arterial embolism might be less relevant in SCD-related ischemic stroke, and other factors like small vessel disease or sickle cell-induced microvascular blood clotting have to be considered.

Pallidal and thalamic deep brain stimulation in myoclonus-dystonia.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus-dystonia (MD). We investigated short- and long-term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi- and VIM-DBS in MD. Ten MD-patients (nine epsilon-sarcoglycan-mutation-positive) were evaluated pre- and post-surgically following continuous bilateral GPi- and VIM-DBS at four time points: presurgical, 6, 12, and as a last follow-up at a mean of 62.3 months postsurgically, and in OFF-, GPi-, VIM-, and GPi-VIM-DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke-Fahn-Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL-scores. MD-symptoms significantly improved at 6 months post-surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long-term evaluation post-surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long-lasting stimulation-related adverse events (AEs) were observed. Both GPi- and VIM-DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation-induced events of GPi-DBS in comparison with VIM-DBS, GPi-DBS seems to be preferable. Combined GPi-VIM-DBS can be useful in cases of incapaciting myoclonus, refractory to GPi-DBS alone.

Increased beta activity in dystonia patients after drug-induced dopamine deficiency.

Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinson's disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (<12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinson's disease.

Brain parenchyma sonography and 123I-FP-CIT SPECT in Parkinson's disease and essential tremor.

We aimed to investigate the accuracy of transcranial brain parenchyma sonography (TCS) for differentiation between idiopathic Parkinson's disease (PD) and essential tremor (ET) in comparison to (123)I-FP-CIT SPECT (FP-CIT SPECT). Seventy-four patients, in whom PD or ET was suspected on the basis of clinical criteria, were analyzed. The echogenicity of the substantia nigra (SN) and the striatal binding of dopamine transporters (DAT) were evaluated by TCS and FP-CIT SPECT, respectively. Three patients were excluded due to an insufficient transtemporal bone window using TCS. Forty-six and 25 patients were clinically classified as PD and ET. SPECT revealed a reduced DAT binding in 42 of all 71 included patients. Thirty-six of the 42 patients with abnormal FP-CIT SPECT findings had a pathological SN hyperechogenicity, whereas TCS findings in the remaining 6 patients were normal. In 27 of 29 patients with normal SPECT findings the SN echogenicity was regular. Referring to FP-CIT SPECT, the sensitivity and specificity of TCS for detection of PD were 86 and 93%; the positive and negative predictive values were 95 and 82%, respectively. Sensitivity and specificity in detection of clinically diagnosed PD patients were 78 and 92% for TCS and 91 and 100% for FP-CIT SPECT, respectively. In patients with pathological FP-CIT SPECT and pathological TCS, the extent of SN hyperechogenicity did not correlate with the degree of reduction in dopamine transporter binding on the side opposite of the more affected limb. TCS allows a reliable differentiation of PD and ET. The TCS SN hyperechogenicity does not correlate with the extent of dopaminergic neuron degeneration.

Subthalamic gamma activity in patients with Parkinson's disease.

Depth recordings in patients with Parkinson's disease (PD) have demonstrated oscillatory activity in the gamma frequency (60-100 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesised to contribute to movement preparation, it is unclear to what extent these LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the STN in PD patients during functional neurosurgery. Eight sides in seven patients out of 15 sides in 12 patients were identified that had peaks in the gamma band in spectra of LFPs. As microelectrodes descended towards STN, there was a pronounced increase in gamma frequency band LFP activity 1 mm above the line joining the anterior and posterior commissures and 2 mm above the microelectrode defined dorsal border of the STN. Gamma activity dropped again 3 mm below the microelectrode defined dorsal border of the STN. Spike-triggered averages of LFP activity suggested that the discharges of neurons in this region were locked to gamma oscillations in the LFP. Gamma band oscillations in the LFP are therefore likely to represent synchronous activity in populations of neurons in the upper STN and bordering zona incerta of patients with PD.

The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease.

Depth recordings in patients with Parkinson's disease (PD) have demonstrated prominent oscillatory activity in the beta frequency (13-35 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesized to contribute to bradykinesia, it is unclear to what extent the LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded both LFPs and multi-neuronal activity from microelectrodes inserted into STN in six PD patients (8 sides) during functional neurosurgery. As microelectrodes passed from above STN into STN, there was a pronounced increase in beta frequency band LFP activity. Furthermore, spike-triggered averages of LFP activity suggested that the discharges of neurons in STN were locked to beta oscillations in the LFP. The LFP is therefore likely to represent synchronous activity in populations of neurons in the STN of patients with PD.

Cellular and network properties of the subiculum in the pilocarpine model of temporal lobe epilepsy.

The subiculum was recently shown to be crucially involved in the generation of interictal activity in human temporal lobe epilepsy. Using the pilocarpine model of epilepsy, this study examines the anatomical substrates for network hyperexcitability recorded in the subiculum. Regular- and burst-spiking subicular pyramidal cells were stained with fluorescence dyes and reconstructed to analyze seizure-induced alterations of the dendritic and axonal system. In control animals burst-spiking cells outnumbered regular-spiking cells by about two to one. Regular- and burst-spiking cells were characterized by extensive axonal branching and autapse-like contacts, suggesting a high intrinsic connectivity. In addition, subicular axons projecting to CA1 indicate a CA1-subiculum-CA1 circuit. In the subiculum of pilocarpine-treated rats we found an enhanced network excitability characterized by spontaneous rhythmic activity, polysynaptic responses, and all-or-none evoked bursts of action potentials. In pilocarpine-treated rats the subiculum showed cell loss of about 30%. The ratio of regular- and burst-spiking cells was practically inverse as compared to control preparations. A reduced arborization and spine density in the proximal part of the apical dendrites suggests a partial deafferentiation from CA1. In pilocarpine-treated rats no increased axonal outgrowth of pyramidal cells was observed. Hence, axonal sprouting of subicular pyramidal cells is not mandatory for the development of the pathological events. We suggest that pilocarpine-induced seizures cause an unmasking or strengthening of synaptic contacts within the recurrent subicular network.

Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis.

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mm) and whether the experimental activity differs according to the presence of aberrant mossy fibers. We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mm K+. They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250-300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mm K+. In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca2+]o. Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K+-induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.

Deep brain stimulation in dystonia.

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.