Dystonic Symptoms Research Articles

High prevalence of olfactory dysfunction in cervical dystonia

IntroductionOlfactory 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). MethodsIn 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. Results58 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. ConclusionsOur 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.

Association analysis of single nucleotide polymorphisms near the DYT3 locus to dystonic symptoms in X-linked dystonia-parkinsonism (S30.008)

Association analysis of single nucleotide polymorphisms near the DYT3 locus to dystonic symptoms in X-linked dystonia-parkinsonism (S30.008)

GABAA Receptor Availability Changes Underlie Symptoms in Isolated Cervical Dystonia.

GABAA receptor availability changes within sensorimotor regions have been reported in some isolated forms of dystonia. Whether similar abnormalities underlie symptoms in cervical dystonia is not known. In the present study, a total of 15 cervical dystonia patients and 15 age- and sex-matched controls underwent 11C-flumazenil PET/CT scanning. The density of available GABAA receptors was estimated using a Simplified Reference Tissue Model 2. Group differences were evaluated using a two-sample T-test, and correlations with dystonia severity, as measured by the Toronto Western Spasmodic Torticollis Rating Scale, and disease duration were evaluated using a regression analysis. Voxel-based analyses revealed increased GABAA availability within the right precentral gyrus in brain motor regions previously associated with head turning and the left parahippocampal gyrus. GABAA availability within the bilateral cerebellum was negatively correlated with dystonia severity, and GABAA availability within the right thalamus and a variety of cerebellar and cortical regions were negatively correlated with disease duration. While GABAA availability changes within primary motor areas could represent a partial compensatory response to loss of inhibition within sensorimotor network, GABAergic signaling impairment within the cerebellum may be a key contributor to dystonia severity.

Treatment of Dystonia Caused by Several Etiologies with DBS

Introduction: This meta-analysis of reported cases of deep brain stimulation (DBS) for dystonia evaluates the effect using the globus pallidus internus (GPi) as target, and the factors that significantly have influenced the outcome related to the target. The Burke-Fahn-Marsden (BFM) movement scale, the most reported measure, was chosen as the primary outcome measure for this analysis. Material and Methods: MEDLINE searches on English literature identified 137 patients who underwent DBS for dystonia in 24 studies that had individual BFM scores. The study was done with statistical analysis by intention to treat. Statistical analysis was made with a significant p-value of 0.05. For the comparison of pre- and postoperative scores, a Wilcoxon signed-rank test was used. Results: The mean BFM percentage change (improvement in postoperative score from baseline) was 46.3% (range 34% to 100%). At last follow-up, disease severity and degree of disability and pain on the BFM were significantly improved by 70.4%, and 67.8%, respectively (p &lt; 0.05, Wilcoxon signed-rank test). Significantly better outcomes were achieved with stimulation of the GPI than with stimulation of the posterior portion of the ventral lateral (VLp) nucleus of the thalamus (p &lt; 0.05). The etiology of the dystonia also had a significant effect on outcomes. Statistically significant improvements in outcomes were seen for all etiologic categories, except encephalitis. Dystonia due to birth injury and encephalitis had significantly worse outcomes of patients who were DYT1, or had pantothenate-kinase-associated neurodegeneration (PKAN), tardive dyskinesia, and idiopathic and posttraumatic dystonias. Longer duration of dystonia symptoms correlated negatively with surgical outcome. Conclusion: Deep Brain Stimulation of the GPi provides improvement in BFM scores in a variety of dystonic conditions.

O-3-5. Beta oscillation in the thalamic Vim single unit activities is not predominant in upper limb dystonia

Thalamic Vim is a relay nucleus from the cerebellum and one of the targets for relieving symptoms of upper limb dystonia as well as tremor-dominant Parkinson’s disease (PD) and essential tremor (ET). Beta oscillation is reported to be predominant from the single unit analysis in this nucleus in PD, ET and chronic pain (Basha D et al., 2014). We analyzed the Vim oscillation at rest in five cases with upper limb dystonia (four females, mean age of 31.2 yo) to elucidate whether beta oscillation is predominant also in dystonia. Single unit activities were recorded with microelectrodes during stereotactic surgery while the patients were awake. Each single unit was identified(?) with template matching method at sites where ablation or deep brain stimulation were effective. In results, the spike frequency in the beta range was not predominant (beta: 14–30 Hz 29 ± 7% (SD), below theta: 3–7 Hz 31 ± 13%, alpha: 8–13 Hz 20 ± 10%, gamma: above 31 Hz 20 ± 18%, n = 33). In dystonia, oscillation pattern at rest in Vim is abnormal in Vim but beta oscillation is not predominant, demonstrating a distinctive pattern from those in PD, ET, and chronic pain.

Influence of electromagnetic radiations of the radio-frequency range on vegetative maintenance of cardiovascular reactions of the human body

With the help of questionnaires, medical exam and functional examination of students was found a positive correlation between the formation of vagotonic reactions of the cardiovascular system and the exposure time of the EMR radio frequency range, as well as the appearance of signs of neurocirculatory dystonia and other pre-nosological symptoms of adverse effects radio waves.

A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

Mutations in SLC39A14 cause a recessive disorder of manganese (Mn) metabolism that manifests as childhood onset progressive neurodegeneration characterized by parkinsonism and dystonia. The present study genetically investigated a case of hypermanganesemia. We describe a family where an affected child with a history of progressive neurodegeneration showed symptoms of dystonia with increased levels of blood Mn and altered signal intensities in globus pallidus and dentate nucleus. Whole exome sequencing was conducted to genetically investigate the pathology in the child, which allowed us to identify a novel homozygous causal mutation in SLC39A14. Insilico modeling of the novel homozygous causal mutation in SLC39A14 predicted that it was deleterious, affecting Mn binding and transportation of metal by transmembrane instability of the protein structure. The clinical features of other reported mutations in SLC39A14 were also reviewed and the clinical spectrum in our case conforms to the described neurological abnormalities. We conclude that the mutation identified in SLC39A14 in our case is a novel variation linked to recessive disorders of hypermaganesemia and dystonia.

A novel SGCE gene mutation in a Moroccan sporadic case with myoclonus-dystonia syndrome

Inherited myoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by myoclonic jerks and dystonia accompanied with psychiatric manifestations that begin in the first two decades of life. Mutations in epsilon-sarcoglycan (SGCE) gene which encodes the SGCE protein represent a major genetic cause of MDS. We report a sporadic MDS case with abnormal movements including myoclonus and dystonic symptoms affecting the upper body then the neck. In addition, obsessive compulsive disorder (OCD) was observed. This heterogeneous phenotype was shown to be associated with a novel heterozygous mutation within the exon 6 of SGCE gene (c.812G>T).

Relationships between Serotonin Transporter Binding in the Raphe Nuclei, Basal Ganglia, and Hippocampus with Clinical Symptoms in Cervical Dystonia: A [11C]DASB Positron Emission Tomography Study.

Alterations of the central serotonergic system have been implicated in the pathophysiology of dystonia. In this molecular imaging study, we assessed whether altered presynaptic serotonin transporter (SERT) binding contributes to the pathophysiology of cervical dystonia (CD), concerning both motor and non-motor symptoms (NMS). We assessed the non-displaceable binding potential (BPND) using the selective SERT tracer [11C]DASB and positron emission tomography (PET) in 14 CD patients and 12 age- and gender-matched controls. Severity of motor symptoms was scored using the Toronto Western Spasmodic Torticollis Rating Scale and Clinical Global Impression jerks/tremor scale. NMS for depressive symptoms, anxiety, fatigue, and sleep disturbances were assessed with quantitative rating scales. The relationship between SERT binding and clinical patient characteristics was analyzed with the Spearman's rho test and multiple regression. When comparing the CD patients with controls, no significant differences in BPND were found. Higher BPND in the dorsal raphe nucleus was statistically significantly correlated (p < 0.001) with motor symptom severity (rs = 0.65), pain (rs = 0.73), and sleep disturbances (rs = 0.73), with motor symptom severity being the most important predictor of SERT binding. Furthermore, fatigue was negatively associated with the BPND in the medial raphe nucleus (rs = -0.61, p = 0.045), and sleep disorders were positively associated with the BPND in the caudate nucleus (rs = 0.58, p = 0.03) and the hippocampus (rs = 0.56, p = 0.02). Motor symptoms, as well as pain, sleep disturbances, and fatigue in CD showed a significant relationship with SERT binding in the raphe nuclei. Moreover, fatigue showed a significant relationship with the medial raphe nucleus and sleep disorders with the caudate nucleus and hippocampus. These findings suggest that an altered serotonergic signaling in different brain areas in CD is related to different motor as well as NMS, which will further stimulate research on the role of serotonin in the pathogenesis of dystonia.

Basic and Translational Neuroscience of Childhood-Onset Dystonia: A Control-Theory Perspective.

Dystonia is a collection of symptoms with involuntary muscle activation causing hypertonia, hyperkinetic movements, and overflow. In children, dystonia can have numerous etiologies with varying neuroanatomic distribution. The semiology of dystonia can be explained by gain-of-function failure of a feedback controller that is responsible for stabilizing posture and movement. Because postural control is maintained by a widely distributed network, many different anatomic regions may be responsible for symptoms of dystonia, although all features of dystonia can be explained by uncontrolled activation or hypersensitivity of motor cortical regions that can cause increased reflex gain, inserted postures, or sensitivity to irrelevant sensory variables. Effective treatment of dystonia in children requires an understanding of the relationship between etiology, anatomy, and the specific mechanism of failure of postural stabilization.

Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease

IntroductionPharmacological treatment of chorea in Huntington's disease (HD) is often limited by poor efficacy or side effects. Pallidal deep brain stimulation (DBS) has been considered in these patients but experience is so far limited. MethodsWe prospectively evaluated the effects of bilateral DBS of the Globus pallidus internus (GPi) over one year in six severely affected HD patients with treatment refractory chorea in an advanced stage of the disease. Primary endpoint of the study was improvement in chorea. Additionally, we evaluated the effects of GPi DBS on the motor part of the Unified Huntington's Disease Rating Scale (UHDRS), bradykinesia, dystonia, functional impairment, psychiatric and cognitive symptoms. Side effects were systematically assessed. ResultsThe chorea subscore was significantly reduced postoperatively (−47% six months, −40% twelve months postoperatively). The UHDRS total motor score was significantly reduced at six months postoperatively (- 17%) but the effect was not sustained twelve months after the operation (- 5%). Pallidal DBS did not improve other motor symptoms or functional impairment. There was no effect on psychiatric symptoms or cognition. A number of side effects were noted, especially spasticity in three of the patients. ConclusionsPallidal DBS is a treatment option for HD patients with severe pharmacologically refractory chorea. Further studies are needed to define optimal candidates for this procedure.

Manganese metabolism in humans.

Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.

Non-motor symptoms in childhood dystonia? New perspectives.

This commentary is on the systematic review by Coenen et al. on pages 244–255 of this issue.

Metoclopramide-induced acute dystonic reaction misinterpreted as conversion disorder and seizure

Metoclopramide, an antiemetic, is the most common cause of drug-induced dystonic reactions. 20-year-old female patient, complaining of involuntary bilateral upward medial deviation of the eyes, generalized muscle contractions and uncontrollable cry was brought into the emergency department(ED) by an ambulance. The diagnosis of the ambulance crew was conversion or seizure. The patient has all of dystonic reaction symptoms, including facial, neck, back, and extremity spasms, opisthotonus, oculogyric crisis, torticollis, trismus. The history revealed 40 mg of metoclopramide intake. Biperiden (5 mg) was infused in 100 ml saline. Symptoms were completely resolved. She was discharged from the ED. Drug-induced dystonic reactions can be confused with conversion, seizures, encephalitis, tetanus and hypocalcemic tetany. It is important for emergency physicians to know the drugs that may have dystonic reaction as potential side effects, recognize the clinical presentation of drug-induced dystonic reactions, and properly manage them in the ED.

Botulinum toxin A for patients with orofacial dystonia: prospective, observational, single-centre study

The objective of this study was to demonstrate the efficacy of intramuscular botulinum toxin type A (BTX-A) as a method of controlling the symptoms of focal facial dystonia. A prospective, longitudinal, observational, pre–post (case-series) single-centre study was conducted over a period of 3 months, involving 30 patients with focal dystonia. The patients were enrolled on a first-come, first-served basis. For all patients, the abnormal movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS). The AIMS results were recorded immediately before BTX-A injection (primary predictor variable) and after 3 months (the toxin reaches its maximum effect 2 weeks after injection, and the effect is maintained for 3 months). An improvement in AIMS score was the primary outcome variable. Treatment efficacy was evaluated using the Pearson correlation index with a level of significance of P<0.05. The average age of the study subjects was 70.9±12.7years (20 female, 10 male). The mean dose of BTX-A used was 27.4±20.5U. The mean improvement in AIMS score after treatment was 5.2±4.2. A significant correlation was found between the dose applied and the reduction in AIMS score (P<0.05). BTX-A can be used in the treatment of focal dystonia and provides reproducible results.

A localized pallidal physiomarker in cervical dystonia.

Deep brain stimulation (DBS) allows for direct recordings of neuronal activity from the human basal ganglia. In Parkinson's disease, a disease-specific physiomarker was identified that is now used to investigate adaptive closed-loop stimulation in first studies. In dystonia, such a physiomarker is missing. Pallidal oscillations were recorded from 153 contact pairs in 27 patients. We investigated whether power amplitudes in theta and beta bands correlate with dystonic symptom severity across patients. We then projected theta power from each contact pair onto standard subcortical anatomy. In this way, we defined a theta hot spot on a group level and investigated whether proximity of the active DBS contacts to it correlated with clinical improvement. Dystonic symptom severity significantly correlated with theta but not beta oscillatory amplitudes (ρ = 0.4, p = 0.009) and interhemispheric coherence (ρ = 0.5, p = 0.002). The sweet spot of theta activity localized to the posterior third of the internal pallidum and theta power correlated with proximity to this location (ρ = 0.23, p = 0.002), which coincided with 3 previously published coordinates describing optimal stimulation targets. Finally, motor improvement through pallidal long-term DBS correlated with theta peak amplitude (ρ = 0.38, p = 0.018). Our findings suggest that theta oscillations in the internal pallidum are robustly associated with dystonic symptoms in cervical dystonia and may be a useful biomarker for adaptive closed-loop stimulation. Furthermore, theta oscillatory activity may have a predictive value for the clinical benefit after chronic DBS that could be used to improve intraoperative neurophysiological target mapping during electrode implantation. Ann Neurol 2017;82:912-924.

Dystonic Camptocormia: Clinical Presentation, Diagnosis, and Treatment Results

This study was aimed at assessing clinical features of camptocormia as one of the dystonia symptoms and evaluating the efficacy of various treatments for this condition. The study involved 39 patients with dystonia and camptocormia symptoms. We analyzed the clinical features of dystonic camptocormia and evaluated the results of pharmacotherapy and botulinum therapy as well as neuromodulation methods, namely transcranial magnetic stimulation and deep brain stimulation. A phased and integrated approach was shown to be required for managing patients with camptocormia caused by dystonic hyperkinesis. Local botulinum toxin injections and deep brain stimulation are the most effective treatments. More extensive use of low-frequency transcranial magnetic stimulation may be advisable for everyday practical use in patients with dystonic camptocormia.

An unusual presentation of tyrosine hydroxylase deficiency

BackgroundDopa-responsive dystonia (DRD) has largely been associated with autosomal dominant mutations in the GCH1 gene leading to GTP cyclohydrolase 1 deficiency. More recently, a deficiency in tyrosine hydroxylase (TH) has been recognized to cause DRD. This is a rare disorder resulting from genetic mutations in the TH gene on chromosome 11. The phenotype ranges from DRD with complete resolution on levodopa to infantile parkinsonism and encephalopathy only partially responsive to levodopa. Here we discuss an adult with TH deficiency with a history of possible parkinsonism and dystonia responsive to levodopa, notable for a residual dynamic segmental dystonia.Case presentationOur patient grew up in rural Myanmar with limited medical care. Childhood was normal except for episodic illness with difficulty moving and speaking. At 18 years he developed difficulty writing. At 21 years he could not speak, walk, or write and was taken to a city hospital. Multiple medications were tried without benefit until he received carbidopa/levodopa, to which he had a miraculous response. Since then he has attempted to come off medication, however after several weeks his symptoms returned. On presentation to us at 31 years he was taking 450 mg levodopa/day and 4 mg trihexyphenidyl/day. He had a dynamic dystonia in his neck and trunk, subtle at rest and prominent with walking. He exhibited a sensory trick when touching his hand to his chin; improvement occurred to a lesser degree when he imagined touching his chin, and to an even lesser degree when the examiner touched his chin. He had no parkinsonism. He underwent genetic testing which revealed a homozygous variant mutation in the TH gene (p.Thr494Met) leading to a diagnosis of autosomal recessive tyrosine hydroxylase deficiency.ConclusionsTH deficiency can cause a broad range of clinical symptoms and severity. As more cases are discovered, the phenotype expands. Here we describe a unique case of DRD and possible parkinsonism due to TH deficiency with residual symptoms of dystonia that was task dependent and responded to a sensory trick. In addition, while the history is limited, it is possible he may have had episodes similar to “lethargy-irritability crises” seen in more severe cases. In large part he fits within the milder form of TH hydroxylase deficiency.

Temporal Discrimination: Mechanisms and Relevance to Adult-Onset Dystonia.

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test–retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis.

Treatment of generalized dystonia by deep brain stimulation

Objective To evaluate the efficacy of deep brain stimulation in treatment of generalized dystonia. Methods A retrospective analysis was conducted on 20 patients who were implanted with a PINS device at Department of Neurosurgery, Peking Union Medical College Hospital from July 2013 to September 2016. Among them, 13 cases were primary generalized dystonia and 7 cases had secondary generalized dystonia. The scores of Burke-Fahn-Marsden dystonia movement/disability were documented at baseline and at 3, 6, 12 months of follow-up. The rate of improvement was assessed at 12 months postoperatively to evaluate the effectiveness of the PINS DBS system. Comparison was conducted regarding the improvement of scores between groups with different targets and parameters of stimulation. Results Compared with preoperative state, the improvement rates of median BFMDRS-M (Burke-Fahn-Marsden Dystonia Rating Scale-Movement) scores were 86.1% and 43.9% in patients with primary and secondary systemic dystonia at 12 months post surgery, respectively. The improvement rates of median BFMDRS-D (Burke-Fahn-Marsden Dystonia Rating Scale-Disability) scores were 66.7% and 44.4%, respectively, and there was significant difference between pre- and post-operative states (both P 0.05). However, the stimulation parameters of STN-DBS group were significantly lower than those of GPi-DBS group (all P<0.05) in terms of voltage, frequency and amplitude. The follow-up lasted 12-48 months. Only 2 cases developed dyskinesia as the adverse event which resolved or obtained improvement by the end of the study. No adverse effects were classified as severe. Conclusions The deep brain stimulation system domestically manufactured could significantly improve the symptoms of generalized dystonia and demonstrates safety and effectiveness. Key words: Deep drain stimulation; Generalized dystonia; Treatment outcome