Tips and tricks in tremor treatment.

Tremor, whether arising from neurological diseases, other conditions, or medication side effects, significantly impacts patients' lives. Treatment complexities necessitate clear algorithms and strategies. Levodopa remains pivotal for Parkinson's tremor, though response variability exists. Some dopamine agonists offer notable tremor reduction targeting D2 receptors. Propranolol effectively manages essential tremor and essential tremor plus (ET/ET +), sometimes with primidone for added benefits, albeit dose-dependent side effects. As reserve medications anticholinergics and clozapine are used for treatment of parkinsonian tremor, 1-Octanol and certain anticonvulsant drugs for tremor of other orign, especially ET. Therapies such as invasive deep brain stimulation and lesional focused ultrasound serve for resistant cases. A medication review is crucial for all forms of tremor, but it is particularly important if medication may have triggered the tremor. Sensor-based detection and non-drug interventions like wristbands and physical therapy broaden diagnostic and therapeutic horizons, promising future tremor care enhancements. Understanding treatment nuances is a key for tailored tremor management respecting patient needs and tolerability. Successful strategies integrate pharmacological, non-invasive, and technological modalities, aiming for optimal symptom control and improved quality of life.

[Improvement of the treatment of patients with spastic movement disorder after stroke]. / Verbesserung der Versorgung von Patientinnen und Patienten mit spastischer Bewegungsstörung nach Schlaganfall.

BACKGROUND: Spastic movement disorder (SMD) develops in up to 43% of cases as a sequela of stroke. In the event of a functionally relevant or daily life impairing SMD or to avoid an impending complication, the medicinal treatment of a focal, multifocal and segmental increase in muscle tone with botulinum neurotoxin A (BoNT-A) is recommended; however, treatment data reveal a lack of guideline-conform treatment with BoNT­A in Germany. OBJECTIVE: The aim of the reported expert meeting was to discuss solutions to the incorrect treatment and undertreatment of patients with SMD and to formulate consensus recommendations to improve the care situation. METHODS: At a consensus meeting held in April 2022, eight experts from the fields of neurology, physical medicine and rehabilitation discussed the causes for the incorrect treatment and undertreatment and formulated consensus solution approaches. RESULTS: Possible reasons for the current incorrect treatment and undertreatment in SMD management in Germany include insufficient awareness of SMD among physicians, a lack of treatment capacities, a lack of information transfer in discharge management as well as staff shortages in the specialized inpatient and outpatient SMD treatment centers. The committee therefore recommended a patient pathway in which affected patients with SMD are provided with correctly implemented BoNT­A treatment in combination with physical measures. CONCLUSION: The recommended treatment pathway for use in stroke patients is intended to close gaps in care and thus ensure guideline-conform treatment of post-stroke SMD.

Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children-update and practice recommendations.

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

Aneurysmal Subarachnoid Hemorrhage during the Shutdown for COVID-19.

The aim was to evaluate hospitalization rates for aneurysmal subarachnoid hemorrhage (SAH) within an interdisciplinary multicenter neurovascular network (NVN) during the shutdown for the COVID-19 pandemic along with its modifiable risk factors. In this multicenter study, admission rates for SAH were compared for the period of the shutdown for the COVID-19 pandemic in Germany (calendar weeks (cw) 12 to 16, 2020), the periods before (cw 6-11) and after the shutdown (cw 17-21 and 22-26, 2020), as well as with the corresponding cw in the years 2015-2019. Data on all-cause and pre-hospital mortality within the area of the NVN were retrieved from the Department of Health, and the responsible emergency medical services. Data on known triggers for systemic inflammation, e.g., respiratory viruses and air pollution, were analyzed. Hospitalizations for SAH decreased during the shutdown period to one-tenth within the multicenter NVN. There was a substantial decrease in acute respiratory illness rates, and of air pollution during the shutdown period. The implementation of public health measures, e.g., contact restrictions and increased personal hygiene during the shutdown, might positively influence modifiable risk factors, e.g., systemic inflammation, leading to a decrease in the incidence of SAH.

[Treatment of Sialorrhea with Botulinum Neurotoxin Type A - Consensus Practice Recommendations for Children and Adults]. / Behandlung der Sialorrhoe mit Botulinum Neurotoxin Typ A ­ Konsentierte Praxisempfehlungen für Kinder und Erwachsene.

Sialorrhea, uncontrolled, excessive drooling, accompanies different, mostly neurological disorders from childhood to adulthood. With incobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH), an approved medication for the treatment of sialorrhea has been available since 2019. Patient selection, possible therapy goals, treatment and the management of specific treatment situations build the focus of this interdisciplinary expert consensus recommendations with the intent to facilitate access to treatment and to contribute to qualified botulinum toxin therapy.

Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia.

BACKGROUND AND OBJECTIVES: Our objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants. METHODS: In-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280). RESULTS: Six different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10-4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10-6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient. DISCUSSION: Our data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

Recurrent Pontine Strokes in a Young Male.

A 34-year-old patient presented to the emergency department with recurrent neurologic symptoms of sudden onset. MRI showed white matter hyperintensities consistent with small vessel disease, predominantly in the pons. There were no known cardiovascular risk factors (CVRF) and extensive workup for vasculitis was negative. The preliminary diagnosis was small vessel primary central nervous system vasculitis, but immunosuppressive treatment did not stop a progression of the disease over 6 months. Repeated negative diagnostic workup for vasculitis, lack of response to therapy, young age, and predominant involvement of the pons were compatible with pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), which is a very rare monogenic cause of cerebral small vessel disease due to upregulation of collagen type-IV. Correspondingly, a COL4A1 mutation was found. Therapy was immediately stopped in favour of more strict adjustment of the CVRF including lowering of LDL < 70 mg/dl and extensive monitoring of blood-pressure.

Disentangling motor planning and motor execution in unmedicated de novo Parkinson's disease patients: An fMRI study.

Many studies have used functional magnetic resonance imaging to unravel the neuronal underpinnings of motor system abnormalities in Parkinson's disease, indicating functional inhibition at the level of basal ganglia-thalamo-cortical motor networks. The study aim was to extend the characterization of functional motor changes in Parkinson's Disease by dissociating between two phases of action (i.e. motor planning and motor execution) during an automated unilateral finger movement sequence with the left and right hand, separately. In essence, we wished to identify neuronal dysfunction and potential neuronal compensation before (planning) and during (execution) automated sequential motor behavior in unmedicated early stage Parkinson's Disease patients. Twenty-two Parkinson's Disease patients (14 males; 53 ±â€¯11 years; Hoehn and Yahr score 1.4 ±â€¯0.6; UPDRS (part 3) motor score 16 ±â€¯6) and 22 healthy controls (14 males; 49 ±â€¯12 years) performed a pre-learnt four finger sequence (index, ring, middle and little finger, in order), either self-initiated (FREE) or externally triggered (REACT), within an 8-second time window. Findings were most pronounced during FREE with the clinically most affected side, where motor execution revealed significant underactivity of contralateral primary motor cortex, contralateral posterior putamen (sensorimotor territory), ipsilateral anterior cerebellum / cerebellar vermis, along with underactivity in supplementary motor area (based on ROI analyses only), corroborating previous findings in Parkinson's Disease. During motor planning, Parkinson's Disease patients showed a significant relative overactivity in dorsolateral prefrontal cortex (DLPFC), suggesting a compensatory overactivity. To a variable extent this relative overactivity in the DLPFC went along with a relative overactivity in the precuneus and the ipsilateral anterior cerebellum/cerebellar vermis Our study illustrates that a refined view of disturbances in motor function and compensatory processes can be gained from experimental designs that try to dissociate motor planning from motor execution, emphasizing that compensatory mechanisms are triggered in Parkinson's Disease when voluntary movements are conceptualized for action.

High prevalence of olfactory dysfunction in cervical dystonia.

INTRODUCTION: Olfactory dysfunction has been established as a frequent non-motor symptom in neurodegenerative and movement disorders such as Parkinson's disease, Alzheimer's disease, and hereditary ataxias. To expand knowledge of non-motor symptoms in dystonia, and to test for a potential endophenotype, we examined olfactory function in cervical dystonia (CD). METHODS: In patients with CD, and neurologically healthy controls, olfactory function was examined by "Sniffin' Sticks", a test of nasal chemosensory function based on pen-like odor dispensing devices. This test enables to define an individual's odor threshold, odor discrimination, and odor identification. Owing to the etiological heterogeneity of olfactory dysfunction, strict exclusion criteria were applied, especially smoking, and sinonasal disease. RESULTS: 58 CD patients completed the study. Olfactory dysfunction was present in 29 patients (50.0%), significantly more frequent than in two groups of matched healthy control subjects (20.7%; 22.4%; p = 0.001). Analysis of the pattern of hyposmia revealed that odor threshold (p = 0.002), and odor identification (p < 0.001) were significantly worse in CD patients compared to controls, while odor discrimination was unchanged. Higher age was the only clinical characteristic to correlate with olfactory dysfunction in CD. CONCLUSIONS: Our observations establish olfactory dysfunction, possibly of both peripheral and central origin, as a new non-motor, and probably motor-unrelated, symptom of CD. Additionally, the potential involvement of cerebellar functions in olfactory identification and discrimination tasks, as well as in pathophysiology of dystonia, justifies further studies of olfactory dysfunction as a possible endophenotype in dystonia.

Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy.

Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.

Depression in blepharospasm: a question of facial feedback?

Depression is the most important nonmotor symptom in blepharospasm (BL). As facial expression influences emotional perception, summarized as the facial feedback hypothesis, we investigated if patients report fewer depressive symptoms if injections of botulinum neurotoxin (BoNT) include the "grief muscles" of the glabellar region, compared to treatment of orbicularis oculi muscles alone. Ninety BL patients were included, half of whom had BoNT treatment including the frown lines. While treatment pattern did not predict depressive symptoms overall, subgroup analysis revealed that in male BL patients, BoNT injections into the frown lines were associated with remarkably less depressive symptoms. We hypothesize that in BL patients presenting with dystonia of the eyebrow region, BoNT therapy should include frown line application whenever justified, to optimize nonmotor effects of BoNT denervation.

Botulinum toxin therapy for treatment of spasticity in multiple sclerosis: review and recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders task force.

Botulinum toxin (BT) therapy is an established treatment of spasticity due to stroke. For multiple sclerosis (MS) spasticity this is not the case. IAB-Interdisciplinary Working Group for Movement Disorders formed a task force to explore the use of BT therapy for treatment of MS spasticity. A formalised PubMed literature search produced 55 publications (3 randomised controlled trials, 3 interventional studies, 11 observational studies, 2 case studies, 35 reviews, 1 guideline) all unanimously favouring the use of BT therapy for MS spasticity. There is no reason to believe that BT should be less effective and safe in MS spasticity than it is in stroke spasticity. Recommendations include an update of the current prevalence of MS spasticity and its clinical features according to classifications used in movement disorders. Immunological data on MS patients already treated should be analysed with respect to frequencies of MS relapses and BT antibody formation. Registration authorities should expand registration of BT therapy for spasticity regardless of its aetiology. MS specialists should consider BT therapy for symptomatic treatment of spasticity.

Central Pain Processing in Early-Stage Parkinson's Disease: A Laser Pain fMRI Study.

BACKGROUND & OBJECTIVE: Pain is a common non-motor symptom in Parkinson's disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson's disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels. METHODS: 13 right-handed early-stage Parkinson's disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale. RESULTS: No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson's disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson's disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex. CONCLUSION: Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson's disease. On the other hand, they argue against a genuine pain-specific processing abnormality in early-stage Parkinson's disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced stages of Parkinson's disease.