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Current Opinion in Neurology Aug 2023The purpose is to review the results and impact of recent studies for current and future treatment of both motor and non-motor symptoms in Parkinson's disease (PD). (Review)
Review
PURPOSE OF REVIEW
The purpose is to review the results and impact of recent studies for current and future treatment of both motor and non-motor symptoms in Parkinson's disease (PD).
RECENT FINDINGS
New formulations of levodopa further optimize motor fluctuations, allowing for more on-time and less dyskinesia. On demand apomorphine continues to showcase itself as an effective and tolerable tool for treating motor off-periods. Though there are no clear treatment guidelines for PD-related constipation and sleep related disorders, several new agents for these non-motor symptoms show promising preliminary data. Expiratory muscle strength training may represent a useful and cost-effective strategy to alleviate oropharyngeal dysphagia associated with PD. There is evidence to suggest that the use of shorter pulse width and directional deep brain stimulation leads can results in a greater therapeutic window.
SUMMARY
Though no interventions currently exist to significantly modify the disease progression of PD, new studies continue to give insight into optimal symptomatic management. Clinicians should be familiar with expanding the repertoire of tools available to treat the diverse range of symptoms and challenges associated with PD.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Levodopa; Dyskinesias; Disease Progression
PubMed: 37366218
DOI: 10.1097/WCO.0000000000001166 -
Movement Disorders : Official Journal... Aug 2023This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International... (Review)
Review
This document presents a consensus on the diagnosis and classification of isolated cervical dystonia (iCD) with a review of proposed terminology. The International Parkinson and Movement Disorder Society Dystonia Study Group convened a panel of experts to review the main clinical and diagnostic issues related to iCD and to arrive at a consensus on diagnostic criteria and classification. These criteria are intended for use in clinical research, but also may be used to guide clinical practice. The benchmark is expert clinical observation and evaluation. The criteria aim to systematize the use of terminology as well as the diagnostic process, to make it reproducible across centers and applicable by expert and non-expert clinicians. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations, which are incorporated into the current criteria. Three iCD presentations are described in some detail: idiopathic (focal or segmental) iCD, genetic iCD, and acquired iCD. The relationship between iCD and isolated head tremor is also reviewed. Recognition of idiopathic iCD has two levels of certainty, definite or probable, supported by specific diagnostic criteria. Although a probable diagnosis is appropriate for clinical practice, a higher diagnostic level may be required for specific research studies. The consensus retains elements proven valuable in previous criteria and omits aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of iCD expands, these criteria will need continuous revision to accommodate new advances. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Torticollis; Dystonic Disorders; Tremor; Consensus; International Classification of Diseases
PubMed: 36989390
DOI: 10.1002/mds.29387 -
The Lancet. Neurology Aug 2023Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has... (Review)
Review
Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1, SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. Given this extreme clinical and genetic heterogeneity, genome sequencing should become the diagnostic tool of choice but is still not available in many clinical settings. Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.
Topics: Humans; Transcranial Direct Current Stimulation; Cerebellar Ataxia; Spinocerebellar Ataxias; Cerebellum; Ubiquitin-Protein Ligases; RNA-Binding Proteins; Exoribonucleases; Mitochondrial Proteins
PubMed: 37479376
DOI: 10.1016/S1474-4422(23)00068-6 -
Movement Disorders : Official Journal... Mar 2024At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on... (Review)
Review
At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on problems and burdens people with MDs undoubtedly have, we highlight their hidden potentials. Starting with current definitions of Parkinson's disease (PD), dystonia, chorea, and tics, we outline that solely conceiving these phenomena as signs of dysfunction falls short of their complex nature comprising both problems and potentials. Such potentials can be traced and understood in light of well-established cognitive neuroscience frameworks, particularly ideomotor principles, and their influential modern derivatives. Using these frameworks, the wealth of data on altered perception-action integration in the different MDs can be explained and systematized using the mechanism-oriented concept of perception-action binding. According to this concept, MDs can be understood as phenomena requiring and fostering flexible modifications of perception-action associations. Consequently, although conceived as being caught in a (trough) state of deficits, given their high flexibility, people with MDs also have high potential to switch to (adaptive) peak activity that can be conceptualized as hidden potentials. Currently, clinical practice and research in MDs are concerned with deficits and thus the "deep and wide troughs," whereas "scattered narrow peaks" reflecting hidden potentials are neglected. To better delineate and utilize the latter to alleviate the burden of affected people, and destigmatize their conditions, we suggest some measures, including computational modeling combined with neurophysiological methods and tailored treatment. © 2024 International Parkinson and Movement Disorder Society.
Topics: Humans; Movement Disorders; Parkinson Disease; Tics; Dystonia; Chorea
PubMed: 38196315
DOI: 10.1002/mds.29706 -
Annual Review of Physiology Feb 2024Novel variants encoding the BK K channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain... (Review)
Review
Novel variants encoding the BK K channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of -associated symptomology is unknown. This review summarizes patient-associated variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic -linked disease and the neuronal mechanisms currently remain priorities for continued investigation.
Topics: Animals; Humans; Large-Conductance Calcium-Activated Potassium Channels; Channelopathies; Epilepsy; Chorea; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
PubMed: 37906945
DOI: 10.1146/annurev-physiol-030323-042845 -
Cerebellum (London, England) Aug 2023The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the...
The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the involvement of the vermis in the pathophysiology of motor ataxia. Between 1879 and 1889, he reported four cases of tectal tumors that clinically manifested with bilateral ophthalmoplegia and unilateral gait ataxia, culminating in the Cerebellar Classic highlighted here. Nothnagel attributed this clinical syndrome to lesions of the colliculi ("quadrigeminal bodies") and compression of the nuclei of the third cranial nerves, but also left open the possibility of the involvement of neighboring structures, such as the cerebellar vermis. Today, the ataxic component of Nothnagel syndrome is explained by a dorsal midbrain abnormality of either neoplastic or vascular origin, involving the superior cerebellar peduncles, besides the oculomotor nerves.
Topics: Male; Animals; Rabbits; Cerebellar Ataxia; Ataxia; Ophthalmoplegia; Mesencephalon; Cerebellum
PubMed: 35817948
DOI: 10.1007/s12311-022-01437-w -
Practical Neurology May 2024A middle-aged Asian man had gait difficulty progressing over several years. His speech had gradually become slurred with involuntary tongue biting. He was the product of...
A middle-aged Asian man had gait difficulty progressing over several years. His speech had gradually become slurred with involuntary tongue biting. He was the product of a consanguineous marriage with no other relevant family history. MR scan of brain showed bilateral caudate atrophy. Nerve conduction studies showed a predominantly sensory peripheral neuropathy. Serum creatine kinase was slightly elevated but electromyography showed no evidence of myopathy. Three consecutive peripheral blood films were negative for acanthocytes. Whole-genome sequencing confirmed a mutation in gene, consistent with autosomal recessive chorea-acanthocytosis.
Topics: Humans; Male; Neuroacanthocytosis; Middle Aged; Vesicular Transport Proteins; Mutation
PubMed: 38290845
DOI: 10.1136/pn-2023-003981 -
Current Opinion in Neurology Aug 2023Late-onset genetic cerebellar ataxias are clinically heterogenous with variable phenotypes. Several of these conditions are commonly associated with dementia.... (Review)
Review
PURPOSE OF REVIEW
Late-onset genetic cerebellar ataxias are clinically heterogenous with variable phenotypes. Several of these conditions are commonly associated with dementia. Recognition of the relationship between ataxia and dementia can guide clinical genetic evaluation.
RECENT FINDINGS
Spinocerebellar ataxias often present with variable phenotypes that may include dementia. Genomic studies have begun to identify links between incomplete penetrance and such variable phenotypes in certain hereditary ataxias. Recent studies evaluating the interaction of TBP repeat expansions and STUB1 sequence variants provide a framework to understand how genetic interactions influence disease penetrance and dementia risk in spinocerebellar ataxia types 17 and 48. Further advances in next generation sequencing methods will continue to improve diagnosis and create new insights into the expressivity of existing disorders.
SUMMARY
The late-onset hereditary ataxias are a clinically heterogenous group of disorders with complex presentations that can include cognitive impairment and/or dementia. Genetic evaluation of late-onset ataxia patients with dementia follows a systemic testing approach that often utilizes repeat expansion testing followed by next-generation sequencing. Advances in bioinformatics and genomics is improving both diagnostic evaluation and establishing a basis for phenotypic variability. Whole genome sequencing will likely replace exome sequencing as a more comprehensive means of routine testing.
Topics: Humans; Spinocerebellar Ataxias; Ataxia; Spinocerebellar Degenerations; Cerebellar Ataxia; Dementia; Ubiquitin-Protein Ligases
PubMed: 37382141
DOI: 10.1097/WCO.0000000000001170 -
Parkinsonism & Related Disorders May 2024Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to... (Review)
Review
INTRODUCTION
Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to many causes.
METHODS
We reviewed the recent literature to identify newly-recognized causes of chorea, including auto-immune, metabolic, and genetic. We also focused upon developments in mechanisms relating to underlying pathophysiology of certain genetic choreas and advances in therapeutics.
RESULTS
Novel autoantibodies continue to be identified as causes of chorea. Both COVID-19 infection and vaccination are reported to result rarely in chorea, although in some cases causality is not clearly established. Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders. Deep brain stimulation can be successful in certain circumstances.
CONCLUSION
Our understanding of mechanisms underlying this movement disorder continues to advance, however much remains to be elucidated.
Topics: Humans; Chorea; COVID-19; Deep Brain Stimulation; Autoantibodies
PubMed: 38378310
DOI: 10.1016/j.parkreldis.2024.106045 -
Parkinsonism & Related Disorders Dec 2023Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our... (Review)
Review
Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our understanding of this topic. These ataxias encompass various etiologies, including postinfectious cerebellar ataxia, gluten ataxia, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus-ataxia syndrome and primary autoimmune cerebellar ataxia. The increased permeability of the brain-blood barrier could potentially explain the vulnerability of the cerebellum to autoimmune processes. In this manuscript, our objective is to provide a comprehensive review of the most prevalent diseases within this group, emphasizing clinical indicators, pathogenesis, and current treatment approaches.
Topics: Humans; Cerebellar Ataxia; Ataxia; Cerebellum; Opsoclonus-Myoclonus Syndrome
PubMed: 37748994
DOI: 10.1016/j.parkreldis.2023.105861