Highlights • There is increasing evidence that dystonia is a network disorder involving multiple brain regions. • Regions involved include the basal ganglia, cerebellum, thalamus and cortex. • ...Cerebellar involvement likely derives from abnormal output, not loss of output. • The network model leads to several specific and testable hypotheses. • The network model has direct implications for new therapies aimed at specific anatomical targets.
The functional neuroanatomy of dystonia Neychev, Vladimir K; Gross, Robert E; Lehéricy, Stephane ...
Neurobiology of disease,
05/2011, Letnik:
42, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. There are many different clinical manifestations, and many different causes. The ...neuroanatomical substrates for dystonia are only partly understood. Although the traditional view localizes dystonia to basal ganglia circuits, there is increasing recognition that this view is inadequate for accommodating a substantial portion of available clinical and experimental evidence. A model in which several brain regions play a role in a network better accommodates the evidence. This network model accommodates neuropathological and neuroimaging evidence that dystonia may be associated with abnormalities in multiple different brain regions. It also accommodates animal studies showing that dystonic movements arise with manipulations of different brain regions. It is consistent with neurophysiological evidence suggesting defects in neural inhibitory processes, sensorimotor integration, and maladaptive plasticity. Finally, it may explain neurosurgical experience showing that targeting the basal ganglia is effective only for certain subpopulations of dystonia. Most importantly, the network model provides many new and testable hypotheses with direct relevance for new treatment strategies that go beyond the basal ganglia. This article is part of a Special Issue entitled “Advances in dystonia”.
The dystonias are a group of disorders characterized by excessive contraction of muscles leading to abnormal involuntary movements. The clinical manifestations are very heterogeneous, with numerous ...distinct syndromes. The etiologies for dystonia are also heterogeneous with idiopathic, acquired, and inherited forms. Technological advances in genetics over the past two decades have led to a rapid growth in the number of genes associated with dystonia. These genes encode proteins with very diverse biological functions. This review focusses on genes that have contributed to understanding shared biological pathways relevant to specific subgroups of dystonia syndromes. Although many potential shared biological pathways have been proposed, the ones addressed here include defects in dopamine signaling, mitochondrial dysfunction and energy maintenance, toxic accumulation of heavy metals in the brain, and calcium channels and abnormal calcium homeostasis. Elucidation of these and other shared pathways is important for understanding the biological basis for dystonia and for designing novel experimental therapeutics that have the broadest potential for multiple types of dystonia.
Cervical dystonia is defined by excessive contraction of muscles that produce abnormal postures and movements of the head, neck, and sometimes the shoulders. Many affected individuals also have pain, ...local muscle hypertrophy, and/or abnormally increased EMG activity. However, abnormal movements are considered the defining feature.
Three cases are described suggesting that some features of cervical dystonia may occur without abnormal movements. In these cases, the only clinical features are pain, local muscle hypertrophy, or abnormal EMG activity. These features may occur years before abnormal movements emerge, or they may occur coincidentally with dystonia affecting regions other than the neck. In some cases, some features associated with cervical dystonia may occur without any obvious abnormal movements.
Some symptoms of cervical dystonia may occur without abnormal movements of the head or neck. The purpose of this report is not to question current diagnostic criteria for cervical dystonia, but to call attention to a phenomenon that deserves further attention. Such cases may be considered to have a pro-dromal form of cervical dystonia or a formes fruste of cervical dystonia. Whatever diagnostic label is applied, the phenomenon is important to recognize, because symptoms may be readily alleviated with botulinum toxin.
•Symptoms of cervical dystonia may emerge years before abnormal movements can be seen.•Unexplained neck pain maybe a helpful clue for this phenomenon.•Recognition of this phenomenon is relevant because symptoms can be treated with botulinum toxin.
The dystonias are a large and heterogenous group of disorders characterized by excessive muscle contractions leading to abnormal postures and/or repetitive movements. Their clinical manifestations ...vary widely, and there are many potential causes. Despite the heterogeneity, helpful treatments are available for the vast majority of patients. Symptom-based therapies include oral medications, botulinum toxins, and surgical interventions. For some subtypes of dystonia, specific mechanism-based treatments are available. Advances in understanding the biological basis for many types of dystonia have led to numerous recent clinical trials, so additional treatments are likely to become available in the very near future.
Abstract The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to ...deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities.
Botulinum toxin (BoNT) is highly effective in the treatment of cervical dystonia (CD), yet a significant proportion of patients report low levels of satisfaction following treatment and fail to ...follow up for repeated treatments. The goal of this study was to determine the reasons that some patients have unsatisfactory responses. A total of 35 subjects who came to our center requesting alternative treatments due to unsatisfactory responses following BoNT treatment for CD were evaluated. Included were 26 women and 9 men with an average age of 57.1 years (range 25–82 years), and an average duration of illness of 12.5 years (range 1–55 years). Details of unsatisfactory BoNT treatments were methodically collected by a movement specialist using a standardized intake form, including provider subspecialty, product used, the number of satisfactory or unsatisfactory trials, doses given, specific muscles treated, the use of electromyographic guidance, side effects, and tests of resistance. The specialist then provided repeat treatments if indicated, and followed each case until the reasons for unsatisfactory outcomes could be determined. Multiple reasons for unsatisfactory outcomes were found. They included suboptimal BoNT doses, suboptimal muscle targeting, intolerable side effects, complex movement patterns, discordant perceptions, and incorrect diagnoses. Only one patient was functionally resistant to BoNT. Of 32 subjects who received repeat BoNT treatments, 25 (78 %) achieved satisfactory responses after revision of the original treatment plan. These results indicate that the majority of unsatisfactory responses to BoNT treatment of CD were caused by correctible factors and imply a need for improved education regarding optimal treatment methods.
Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and ...kidneys, which are the body's top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since
IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency.
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