Myoclonus dystonia and idiopathic dystonia are associated with a greater frequency of obsessive compulsive disorder (OCD) and major depression. We investigated the frequency of OCD in 39 patients with primary focal hand dystonia (FHD) using a semistructured interview. OCD and subsyndromal OCD was diagnosed in 5 of 39 (12.82%) patients with FHD, whereas OCD occurs in 2.3% of the general population. Recurrent depression occurred in (7 of 39) 17.95% of patients with FHD along with a family history of depression in (16 of 39) 41.02%. Overlapping mechanisms manifesting as FHD may also predispose to OC symptoms and likely implicates a common striatal dysfunction.
obsessive compulsive disorder; depression; dystonia; striatum; obsession; compulsion
The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of “self-agency.” The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the subject feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder.
Twenty patients with motor conversion disorder and 20 age- and gender-matched healthy volunteers used a rotating clock to judge the time of their own voluntary keypresses (action) and a subsequent auditory tone (effect), after completing conditioning blocks in which high, medium and low tones were coupled to images of happy, fearful and neutral faces.
The results replicate those shown previously: an effect following a voluntary action was reported as occurring earlier, and the preceding action later, compared to trials of only keypresses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores.
We show that motor conversion disorder patients have decreased action-effect binding for normal voluntary movements compared to healthy volunteers, consistent with the greater experience of lack of control.
agency; action-effect binding; conversion disorder; psychogenic movement disorder; forward model
Symptomatic animal models have clinical features consistent with human disorders and are often used to identify the anatomical and physiological processes involved in the expression of symptoms and to experimentally demonstrate causality where it would be infeasible in the patient population. Rodent and primate models of dystonia have identified basal ganglia abnormalities, including alterations in striatal GABAergic and dopaminergic transmission. Symptomatic animal models have also established the critical role of the cerebellum in dystonia, particularly abnormal glutamate signaling and aberrant Purkinje cell activity. Further, experiments suggest that the basal ganglia and cerebellum are nodes in an integrated network that is dysfunctional in dystonia. The knowledge gained from experiments in symptomatic animal models may serve as the foundation for the development of novel therapeutic interventions to treat dystonia.
mouse model; primate model; cerebellum; basal ganglia
This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during three in-person meetings and manuscript review by mail.
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along two axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features), and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment.
We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia.
The most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, where the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focussing attention on less well-understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias, as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders, and for developing novel therapeutics.
Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, and in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit pronounced motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. Additionally, conditional knockout mouse models for DYT1 and DYT11 dystonia show that the loss of the causal dystonia related proteins in the striatum lead to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are an extremely powerful tool to elucidate the pathophysiology and to further develop new therapeutics for dystonia.
Dystonia is movement disorder with many diverse underlying etiologies. Some of those etiologies manifest at specific stages of development or at specific ages. Others may present early in life and evolve as the individual develops. Appearance of symptoms during a time of nervous system development poses special challenges to the neurology. Normal functions change appearance, dysfunction may manifest in an age-dependent manner, and age-dependent differences in beneficial and toxic effects of treatments all introduce complexities to the process of diagnosis, functional assessment, and therapeutics. Consideration of these developmental differences is essential in assuring a universal definition of dystonia, valid and reliable assessment tools that can be compared across the lifespan, and more effective therapeutics.
Rating Scales; Development; Treatment; Pediatrics
The dystonias are a group of hyperkinetic movement disorders whose principal cause is neuron dysfunction at one or more interconnected nodes of the motor system. The study of genes and proteins which cause familial dystonia provides critical information about the cellular pathways involved in this dysfunction which disrupts the motor pathways at systems level. In recent years study of the increasing number of DYT genes has implicated a number of cell functions which appear to be involved in the pathogenesis of dystonia.
Review of literature published in English language publications available on Pubmed relating to the genetics and cellular pathology of dystonia
Results and Conclusions
Numerous potential pathogenetic mechanisms have been identified. We describe those which fall into three emerging thematic groups: cell cycle and transcriptional regulation in the nucleus, endoplasmic reticulum and nuclear envelope function, and control of synaptic function.
DYT genes; Cell cycle; endoplasmic reticulum; Nuclear envelope; synaptic function
Psychiatric disorders are highly prevalent in patients with dystonia and have a profound effect on quality of life. Patients with dystonia frequently meet criteria for anxiety disorders, especially social phobia, and major depressive disorder. Deficits in emotional processing have also been demonstrated in some dystonia populations. Onset of psychiatric disturbances in patients with dystonia often precedes onset of motor symptoms suggesting that the pathophysiology of dystonia itself contributes to the genesis of psychiatric disturbances. This article examines the hypothesis that mood and anxiety disorders are intrinsic to the neurobiology of dystonia, citing the available literature, which is derived mostly from research on focal isolated dystonias. Limitations of studies are identified and the role of emotional reactivity, especially in the context of pain secondary to dystonia, is recognized. Available evidence underscores the need to develop dystonia assessment tools that incorporate psychiatric measures. Such tools would allow for a better understanding of the full spectrum of dystonia presentations and facilitate research on the treatment of dystonia as well as the treatment of psychiatric illnesses in the context of dystonia.
dystonia; psychiatry; depression; anxiety; social phobia
Psychogenic movement disorder is defined as abnormal movements unrelated to a medical cause and presumed related to underlying psychological factors. Although psychological factors are of both clinical and pathophysiological relevance, very few studies to date have systematically assessed their role in psychogenic movement disorder. We sought to assess the role of previous life stress using validated quantitative measures in patients with psychogenic movement disorder compared with age- and sex-matched healthy volunteers as well as a convenience sample of patients with focal hand dystonia. Sixty-four patients with psychogenic movement disorder (72% female; mean age, 45.2 years [standard deviation, 15.2 years]), 38 healthy volunteers (74% female; mean age, 49 years [standard deviation, 13.7 years]), and 39 patients with focal hand dystonia (37% female; mean age, 48.7 years [standard deviation, 11.7 years]) were evaluated using a standardized psychological interview as well as validated quantitative scales to assess trauma and previous stressors, depression, anxiety, and personality traits. Patients with psychogenic movement disorder reported higher rates of childhood trauma, specifically greater emotional abuse and physical neglect, greater fear associated with traumatic events, and a greater number of traumatic episodes compared with healthy volunteers and patients with focal hand dystonia controlled for depressive symptoms and sex (Bonferroni corrected P < .005). There were no differences in categorical psychiatric diagnoses or scores on childhood physical or sexual abuse subscales, personality traits, or the dissociative experience scale. Our findings highlight a biopsychosocial approach toward the pathophysiology of psychogenic movement disorder, although the association with psychological issues is much less prominent than expected compared with the nonepileptic seizure population. A careful psychological assessment is indicated to optimize therapeutic modalities.
dystonia; movement disorders; psychogenic; psychological measures; trauma
balance; gait; posture; Parkinson’s disease; freezing of gait
Idiopathic REM sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for PD and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.
Four hundred and eighty-four sleep-clinic– based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria.
We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients, with other sleep diagnoses.
A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.
REM sleep behavior disorder; screening; diagnosis
The pathogenesis of essential tremor is poorly understood. Historically, the inferior olivary nucleus has been hypothesized to play an important role in the generation of tremor in essential tremor, yet a detailed, controlled, anatomic-pathological study of that brain region has yet to be conducted.
A detailed postmortem study was undertaken of the microscopic changes in the inferior olivary nucleus of 14 essential tremor cases vs. 15 age-matched controls at the Essential Tremor Centralized Brain Repository. A series of metrics was used to quantify microscopic neuronal and glial changes in the inferior olivary nucleus and its input and output tracts. Olivary linear neuronal density was also assessed.
Cases and controls did not differ from one another with respect to any of the assessed metrics (p values ranged from 0.23 – 1.0). Olivary linear neuronal density was also similar in cases and controls (p = 0.62). Paddle-shaped neurons, a morphologic shape change in olivary neurons, which to our knowledge have not been previously recognized, occurred to an equal degree in ET cases and controls (p = 0.89), and correlated with several markers of neuronal loss and gliosis.
A systematic postmortem study of the microscopic changes in the inferior olivary nucleus did not detect any differences between cases and controls. These data, along with positron emission tomography data, which have failed to identify any metabolic abnormality of the olive, indicate that if the olive is involved in essential tremor, there is no clearly identifiable structural or metabolic correlate.
essential tremor; brain; pathology; inferior olivary nucleus; pathophysiology; neurodegenerative
Hereditary sensory and autonomic neuropathy type III features a marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26/30. Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7±1.0° and the range was very wide (2.8–18.1°); conversely, absolute error was only 2.7±0.3° (1.6–5.5°) in the controls and 3.0±0.2° (2.1–3.4°) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients, suggesting that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.
congenital insensitivity to pain; familial dysautonomia; joint sense; hereditary sensory & autonomic neuropathy; muscle spindles; proprioception; Riley-Day syndrome
The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treatments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full articles in English between January 2002 and December 2010 were reviewed. Criteria for inclusion and ranking followed the original program outline and adhered to EBM methodology. For efficacy conclusions, treatments were designated: efficacious, likely efficacious, unlikely efficacious, non-efficacious, or insufficient evidence. Safety data were catalogued and reviewed. Based on the combined efficacy and safety assessment, Implications for clinical practice were determined using the following designations: clinically useful, possibly useful, investigational, unlikely useful, and not useful. Fifty-four new studies qualified for efficacy review while several other studies covered safety issues. Updated and new efficacy conclusions were made for all indications. The treatments that are efficacious for the management of the different non-motor symptoms are as follows: pramipexole for the treatment of depressive symptoms, clozapine for the treatment of psychosis, rivastigmine for the treatment of dementia, and botulinum toxin A (BTX-A) and BTX-B as well as glycopyrrolate for the treatment of sialorrhea. The practical implications for these treatments, except for glycopyrrolate, are that they are clinically useful. Since there is insufficient evidence of glycopyrrolate for the treatment of sialorrhea exceeding 1 week, the practice implication is that it is possibly useful. The treatments that are likely efficacious for the management of the different non-motor symptoms are as follows: the tricyclic antidepressants nortriptyline and desipramine for the treatment of depression or depressive symptoms and macrogol for the treatment of constipation. The practice implications for these treatments are possibly useful. For most of the other interventions there is insufficient evidence to make adequate conclusions on their efficacy. This includes the tricyclic antidepressant amitriptyline, all selective serotonin reuptake inhibitors (SSRIs) reviewed (paroxetine, citalopram, sertraline, and fluoxetine), the newer antidepressants atomoxetine and nefazodone, pergolide, Ω-3 fatty acids as well as repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression or depressive symptoms; methylphenidate and modafinil for the treatment of fatigue; amantadine for the treatment of pathological gambling; donepezil, galantamine, and memantine for the treatment of dementia; quetiapine for the treatment of psychosis; fludrocortisone and domperidone for the treatment of orthostatic hypotension; sildenafil for the treatment of erectile dysfunction, ipratropium bromide spray for the treatment of sialorrhea; levodopa/carbidopa controlled release (CR), pergolide, eszopiclone, melatonin 3 to 5 mg and melatonin 50 mg for the treatment of insomnia and modafinil for the treatment of excessive daytime sleepiness. Due to safety issues the practice implication is that pergolide and nefazodone are not useful for the above-mentioned indications. Due to safety issues, olanzapine remains not useful for the treatment of psychosis. As none of the studies exceeded a duration of 6 months, the recommendations given are for the short-term management of the different non-motor symptoms. There were no RCTs that met inclusion criteria for the treatment of anxiety disorders, apathy, medication-related impulse control disorders and related behaviors other than pathological gambling, rapid eye movement (REM) sleep behavior disorder (RBD), sweating, or urinary dysfunction. Therefore, there is insufficient evidence for the treatment of these indications. This EBM review of interventions for the non-motor symptoms of PD updates the field, but, because several RCTs are ongoing, a continual updating process is needed. Several interventions and indications still lack good quality evidence, and these gaps offer an opportunity for ongoing research.
Parkinson's disease; evidence-based medicine; dopamine agonists; tricyclic antidepressants; selective serotonin reuptake inhibitors (SSRIs); omega-3 fatty-acids; transcranial magnetic stimulation
The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson’s disease in the Ashkenazi Jewish population are not well described; therefore we sought to more systematically characterize these features using a semi-structured psychiatric interview and neuropsychological testing.
Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age, sex and gender matched Ashkenazi Jewish Parkinson’s disease patients without mutations.
While overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a six-fold increased risk of pre-morbid affective disorders (OR 6.0, p=0.10) as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders–IV. Of interest, we identified two leucine-rich repeat kinase carriers with bipolar disorder; no mutation negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test- Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups.
Study findings suggest a possible association between pre-morbid mood disorders and leucine-rich repeat kinase Parkinson’s disease warranting further evaluation.
Parkinson’s disease; LRRK2; Mood; Depression; Cognition
Dystonia; Classification; DYT1; THAP1; GNAL
Our previous work showed a beneficial therapeutic effect on blepharospasm using slow repetitive transcranial magnetic stimulation which produces a long-term depression-like effect. High-frequency supraorbital electrical stimulation, asynchronous with the R2 component of the blink reflex, can also induce long-term depression-like effects on the blink reflex circuit in healthy subjects. Patients with blepharospasm have reduced inhibition of their blink recovery curves; therefore, a long-term depression-like intervention might normalize the blink reflex recovery and have a favorable therapeutic effect.
This is a randomized, sham-controlled, observer-blinded prospective study. In 14 blepharospasm patients, we evaluated the effects of high-frequency supraorbital stimulation on three separate treatment days. We applied 28 trains of 9 stimuli, 400 Hertz, either BEFORE or AFTER the R2 or used SHAM stimulation. The primary outcome was the blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after and 1 hour after stimulation while resting, reading, and talking; secondary outcome was the blink reflex recovery.
Stimulation-BEFORE and stimulation-AFTER the R2 both showed a similar improvement as SHAM-stimulation in physician rating, but patients felt significantly better with the BEFORE condition. Improvement in recovery of the blink reflex was seen only in the BEFORE condition. Clinical symptoms differed in the three baseline conditions (resting, reading, talking).
Stimulation BEFORE R2 increased inhibition in trigeminal blink reflex circuits in blepharospasm toward normal values and produced subjective but not objective improvement. Inhibition of the blink reflex pathway by itself appeared to be insufficient for a useful therapeutic effect.
blepharospasm; dystonia; plasticity; clinical trials randomized controlled; blink reflex
Parkinson’s disease; pedunculopontine nucleus; Pisa syndrome; postural abnormality
The search for vulnerability genes for Tourette syndrome has been ongoing for nearly three decades. The contribution of recessive loci with reduced penetrance is one possibility that has been difficult to explore. Homo-zygosity mapping has been successfully used to detect recessive loci within populations with high rates of consanguinity. Using this technique, even quite small inbred families can be informative due to autozygosity in which the two alleles at an autosomal locus are identical by descent (i.e., copies of a single ancestral gene). To explore the utility of this approach, we identified 12 consanguineous Iranian families. Remarkably, these families were seen with an unusual natural history characterized by the early onset of vocal tics and coprolalia and frequent comorbidity with obsessive-compulsive disorder. Genotyping the affected and unaffected members of these pedigrees has the potential to identify rare recessive contributions to this disorder.
Tourette syndrome; homozygosity mapping; recessive inheritance; coprolalia; self-injurious behavior
Tourette syndrome (TS) has a multifactorial etiology, in which genetic, environmental, immunological and hormonal factors interact to establish vulnerability. This review: (i) summarizes research exploring the exposure of TS patients to immune-activating environmental factors, and (ii) focuses on recent findings supporting a role of the innate and adaptive immune systems in the pathogenesis of TS and related disorders. A higher exposure prior to disease onset to group A β-haemolytic streptococcal (GABHS) infections in children with tics and obsessive-compulsive (OC) symptoms has been documented, although their influence upon the course of disease remains uncertain. Increased activation of immune responses in TS is suggested by changes in gene expression profiles of peripheral immune cells, relative frequency of lymphocyte subpopulations, and synthesis of immune effector molecules. Increased activity of cell-mediated mechanisms is suggested by the increased expression of genes controlling natural killer and cytotoxic T cells, increased plasma levels of some pro-inflammatory cytokines which correlate with disease severity, and increased synthesis of antineuronal antibodies. Important methodological differences might account for some inconsistency among results of studies addressing autoantibodies in TS. Finally, a general predisposition to autoimmune responses in TS patients is indicated by the reduced frequency of regulatory T cells, which induce tolerance towards self-antigens. Although the pathogenic role of immune activation in TS has not been definitively proven, a pathophysiological model is proposed to explain the possible effect of immunity upon dopamine transmission regulation and the generation of tics.
group A beta haemolytic Streptococcus; tic; tourette syndrome; autoimmunity; antineuronal antibodies
Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia.
We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson’s Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson’s severity, site, and initial treatment with pramipexole or levodopa.
For subjects who consumed > 12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% confidence interval, 0.37–1.01) compared to subjects who consumed < 4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (C.I. 0.46–1.15) (test for trend, p = 0.05).
These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia.
Caffeine; adenosine; Parkinson’s disease; PD; dyskinesia