Hyperkinetic movement disorders encompass dystonia, tremor, myoclonus, tics, chorea, startle, etc. They present with overlapping clinical features that require clinical expertise and laboratory workout to make a differential diagnosis. Advances in genetics, imaging, neurophysiology, and pathology promise support in the differential diagnosis of hyperkinetic movement disorders. This topic will be devoted to typical and atypical presentations of hyperkinetic movement disorders and to present and future diagnostic tools.

Leiden University Medical Center (LUMC)

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Frontiers in Neurology

Movement Disorders

Diagnostic issues in Hyperkinetic disorders

IntroductionMyoclonus–dystonia (M–D) is a young onset movement disorder typically involving myoclonus and dystonia of the upper body. A proportion of the cases are caused by mutations to the autosomal dominantly inherited, maternally imprinted, epsilon-sarcoglycan gene (SGCE). Despite several sets of diagnostic criteria, identification of patients most likely to have an SGCE mutation remains difficult.</sec>MethodsForty consecutive patients meeting pre-existing diagnostic clinical criteria for M–D underwent a standardized clinical examination (20 SGCE mutation positive and 20 negative). Each video was reviewed and systematically scored by two assessors blinded to mutation status. In addition, the presence and coexistence of myoclonus and dystonia was recorded in four body regions (neck, arms, legs, and trunk) at rest and with action.</sec>ResultsThirty-nine patients were included in the study (one case was excluded owing to insufficient video footage). Based on previously proposed diagnostic criteria, patients were subdivided into 24 “definite,” 5 “probable,” and 10 “possible” M–D. Motor symptom severity was higher in the SGCE mutation-negative group. Myoclonus and dystonia were most commonly observed in the neck and upper limbs of both groups. Truncal dystonia with action was significantly seen more in the mutation-negative group (p < 0.05). Coexistence of myoclonus and dystonia in the same body part with action was more commonly seen in the mutation-negative cohort (p < 0.05).</sec>ConclusionTruncal action dystonia and coexistence of myoclonus and dystonia in the same body part with action might suggest the presence of an alternative mutation in patients with M–D.</sec>

Introduction: Myoclonus–dystonia (M–D) is a young onset movement disorder typically involving myoclonus and dystonia of the upper body. A proportion of the cases are caused by mutations to the autosomal dominantly inherited, maternally imprinted, epsilon-sarcoglycan gene (SGCE). Despite several sets of diagnostic criteria, identification of patients most likely to have an SGCE mutation remains difficult.Methods: Forty consecutive patients meeting pre-existing diagnostic clinical criteria for M–D underwent a standardized clinical examination (20 SGCE mutation positive and 20 negative). Each video was reviewed and systematically scored by two assessors blinded to mutation status. In addition, the presence and coexistence of myoclonus and dystonia was recorded in four body regions (neck, arms, legs, and trunk) at rest and with action.Results: Thirty-nine patients were included in the study (one case was excluded owing to insufficient video footage). Based on previously proposed diagnostic criteria, patients were subdivided into 24 “definite,” 5 “probable,” and 10 “possible” M–D. Motor symptom severity was higher in the SGCE mutation-negative group. Myoclonus and dystonia were most commonly observed in the neck and upper limbs of both groups. Truncal dystonia with action was significantly seen more in the mutation-negative group (p &lt; 0.05). Coexistence of myoclonus and dystonia in the same body part with action was more commonly seen in the mutation-negative cohort (p &lt; 0.05).Conclusion: Truncal action dystonia and coexistence of myoclonus and dystonia in the same body part with action might suggest the presence of an alternative mutation in patients with M–D.

Distribution and Coexistence of Myoclonus and Dystonia as Clinical Predictors of SGCE Mutation Status: A Pilot Study

Resting-state imaging designs are powerful in modeling functional networks in movement disorders because they eliminate task performance related confounds. However, the most common metric for quantifying functional connectivity, i.e., bivariate magnitude coherence (Coh), can sometimes be contaminated by spurious correlations in blood-oxygen level dependent (BOLD) signal due to smoothing and seed blur, thereby limiting the identification of true interactions between neighboring neural populations. Here, we apply a novel functional connectivity metric., i.e., imaginary coherence (ICoh), to BOLD fMRI data in healthy individuals and patients with task-specific focal hand dystonia (tspFHD), in addition to the traditional magnitude Coh metric. We reconstructed resting-state sensorimotor, basal ganglia, and default-mode networks using both Coh and ICoh. We demonstrate that indeed the ICoh metric eliminates spatial blur around seed placement and reflects slightly different networks from Coh. We then identified significant reductions in resting-state connectivity within both the sensorimotor and basal ganglia networks in patients with tspFHD, primarily in the hemisphere contralateral to the affected hand. Collectively, these findings direct our attention to the fact that multiple networks are decoupled in tspFHD that can be unraveled by different functional connectivity metrics, and that this aberrant communication contributes to clinical deficits in the disorder.

Resting-state imaging designs are powerful in modeling functional networks in movement disorders because they eliminate task performance related confounds. However, the most common metric for quantifying functional connectivity, i.e., bivariate magnitude coherence (Coh), can sometimes be contaminated by spurious correlations in blood-oxygen level dependent (BOLD) signal due to smoothing and seed blur, thereby limiting the identification of true interactions between neighboring neural populations. Here, we apply a novel functional connectivity metric., i.e., imaginary coherence (ICoh), to BOLD fMRI data in healthy individuals and patients with task-specific focal hand dystonia (tspFHD), in addition to the traditional magnitude Coh metric. We reconstructed resting-state sensorimotor, basal ganglia, and default-mode networks using both Coh and ICoh. We demonstrate that indeed the ICoh metric eliminates spatial blur around seed placement and reflects slightly different networks from Coh. We then identified significant reductions in resting-state connectivity within both the sensorimotor and basal ganglia networks in patients with tspFHD, primarily in the hemisphere contralateral to the affected hand. Collectively, these findings direct our attention to the fact that multiple networks are decoupled in tspFHD that can be unraveled by different functional connectivity metrics, and that this aberrant communication contributes to clinical deficits in the disorder.

Complex-Value Coherence Mapping Reveals Novel Abnormal Resting-State Functional Connectivity Networks in Task-Specific Focal Hand Dystonia

Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting and repetitive movements and abnormal postures. Several causative genes have been identified, but their genetic bases still remain elusive. Primary Torsion Dystonias (PTDs), in which dystonia is the only clinical sign, can be inherited in a monogenic fashion, and many genes and loci have been identified for autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms. However most sporadic cases, especially those with late-onset, are likely multifactorial, with genetic and environmental factors interplaying to reach a threshold of disease. At present, genetic counseling of dystonia patients remains a difficult task. Recently non-motor clinical findings in dystonias, new highlights in the pathophysiology of the disease, and the availability of high-throughput genome-wide techniques are proving useful tools to better understand the complexity of PTD genetics. We briefly review the genetic basis of the most common forms of hereditary PTDs, and discuss relevant issues related to molecular diagnosis and genetic counseling.

Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting and repetitive movements and abnormal postures. Several causative genes have been identified, but their genetic bases still remain elusive. Primary Torsion Dystonias (PTDs), in which dystonia is the only clinical sign, can be inherited in a monogenic fashion, and many genes and loci have been identified for autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms. However most sporadic cases, especially those with late-onset, are likely multifactorial, with genetic and environmental factors interplaying to reach a threshold of disease. At present, genetic counseling of dystonia patients remains a difficult task. Recently non-motor clinical findings in dystonias, new highlights in the pathophysiology of the disease, and the availability of high-throughput genome-wide techniques are proving useful tools to better understand the complexity of PTD genetics. We briefly review the genetic basis of the most common forms of hereditary PTDs, and discuss relevant issues related to molecular diagnosis and genetic counseling.

Genetic Issues in the Diagnosis of Dystonias

Neuropathology of hyperkinetic movement disorders can be very challenging. This paper starts with basic functional anatomy of the basal ganglia in order to appreciate that focal lesions like for instance tumor or infarction can cause hyperkinetic movement disorders like (hemi)ballism. The neuropathology of different causes of chorea (amongst others Huntington’s disease, neuroacanthosis, and HLD-2) and dystonia (DYT1, PD, and Dopa-Responsive Dystonia) are described. Besides the functional anatomy of the basal ganglia a wider anatomical network view is provided. This forms the basis for the overview of the neuropathology of different forms of tremor.

Neuropathology of hyperkinetic movement disorders can be very challenging. This paper starts with basic functional anatomy of the basal ganglia in order to appreciate that focal lesions like for instance tumor or infarction can cause hyperkinetic movement disorders like (hemi)ballism. The neuropathology of different causes of chorea (amongst others Huntington&#x2019;s disease, neuroacanthosis, and HLD-2) and dystonia (DYT1, PD, and Dopa-Responsive Dystonia) are described. Besides the functional anatomy of the basal ganglia a wider anatomical network view is provided. This forms the basis for the overview of the neuropathology of different forms of tremor.

Neuropathological Diagnostic Considerations in Hyperkinetic Movement Disorders

In task-specific focal hand dystonia (tspFHD), the temporal dynamics of cortical activity in the motor system and how these processes are related to impairments in sensory and motor function are poorly understood. Here, we use time-frequency reconstructions of magnetoencephalographic (MEG) data to elaborate the temporal and spatial characteristics of cortical activity during movement. A self-paced finger tapping task during MEG recording was performed by 11 patients with tspFHD and 11 matched healthy controls. In both groups robust changes in beta (12–30 Hz) and high gamma (65–90 Hz) oscillatory activity were identified over sensory and motor cortices during button press. A significant decrease [p < 0.05, 1% False Discovery Rate (FDR) corrected] in high gamma power during movements of the affected hand was identified over ipsilateral sensorimotor cortex in the period prior to (−575 ms) and following (725 ms) button press. Furthermore, an increase (p < 0.05, 1% FDR corrected) in beta power suppression following movement of the affected hand was identified over visual cortex in patients with tspFHD. For movements of the unaffected hand, a significant (p < 0.05, 1% FDR corrected) increase in beta power suppression was identified over secondary somatosensory cortex (S2) in the period following button press in patients with tspFHD. Oscillatory activity within in the tspFHD group was however not correlated with clinical measures. Understanding these aberrant oscillatory dynamics can provide the groundwork for interventions that focus on modulating the timing of this activity.

In task-specific focal hand dystonia (tspFHD), the temporal dynamics of cortical activity in the motor system and how these processes are related to impairments in sensory and motor function are poorly understood. Here, we use time-frequency reconstructions of magnetoencephalographic (MEG) data to elaborate the temporal and spatial characteristics of cortical activity during movement. A self-paced finger tapping task during MEG recording was performed by 11 patients with tspFHD and 11 matched healthy controls. In both groups robust changes in beta (12–30 Hz) and high gamma (65–90 Hz) oscillatory activity were identified over sensory and motor cortices during button press. A significant decrease [p &lt; 0.05, 1% False Discovery Rate (FDR) corrected] in high gamma power during movements of the affected hand was identified over ipsilateral sensorimotor cortex in the period prior to (−575 ms) and following (725 ms) button press. Furthermore, an increase (p &lt; 0.05, 1% FDR corrected) in beta power suppression following movement of the affected hand was identified over visual cortex in patients with tspFHD. For movements of the unaffected hand, a significant (p &lt; 0.05, 1% FDR corrected) increase in beta power suppression was identified over secondary somatosensory cortex (S2) in the period following button press in patients with tspFHD. Oscillatory activity within in the tspFHD group was however not correlated with clinical measures. Understanding these aberrant oscillatory dynamics can provide the groundwork for interventions that focus on modulating the timing of this activity.

Aberrant Oscillatory Activity during Simple Movement in Task-Specific Focal Hand Dystonia

Hyperkinesias are heterogeneous conditions that share the feature of production of involuntary, abnormal, excessive movements. Tremor, dystonia, and chorea are amongst the most common of these phenomena. In this focused review there is a discussion of difficult issues in hyperkinesias. The first one is the differential diagnosis between essential tremor (ET) and Parkinson’s disease (PD). They are readily distinguishable in the majority of patients but in a few subjects ET coexist with parkinsonian features whose underlying mechanism remains to be determined. The second topic of the review is dystonic tremor. Although increasingly diagnosed and reported as accounting for the majority of scans without evidence of dopaminergic deficits, its diagnostic criteria are ill-defined and differentiation from PD and ET can be challenging. In the last section, there is a discussion of the differential diagnosis of Sydenham’s chorea (SC), the most common cause of chorea in children. In a few patients, vascular disease, systemic lupus erythematosus, and primary antiphospholipid antibody syndrome can mimic SC.

Hyperkinesias are heterogeneous conditions that share the feature of production of involuntary, abnormal, excessive movements. Tremor, dystonia, and chorea are amongst the most common of these phenomena. In this focused review there is a discussion of difficult issues in hyperkinesias. The first one is the differential diagnosis between essential tremor (ET) and Parkinson&#x2019;s disease (PD). They are readily distinguishable in the majority of patients but in a few subjects ET coexist with parkinsonian features whose underlying mechanism remains to be determined. The second topic of the review is dystonic tremor. Although increasingly diagnosed and reported as accounting for the majority of scans without evidence of dopaminergic deficits, its diagnostic criteria are ill-defined and differentiation from PD and ET can be challenging. In the last section, there is a discussion of the differential diagnosis of Sydenham&#x2019;s chorea (SC), the most common cause of chorea in children. In a few patients, vascular disease, systemic lupus erythematosus, and primary antiphospholipid antibody syndrome can mimic SC.

Difficult Diagnoses in Hyperkinetic Disorders – A Focused Review

Background: Tremor is the most prevalent movement disorder in clinical practice. It is defined as involuntary, rhythmic, oscillatory movements. The diagnostic process of patients with tremor can be laborious and challenging, and a clear, systematic overview of available diagnostic techniques is lacking. Tremor can be a symptom of many diseases, but can also represent a distinct disease entity. Objective: The objective of this review is to give a clear, systematic and step-wise overview of the diagnostic work-up of a patient with tremor. The clinical relevance and value of available laboratory tests in patients with tremor will be explored. Methods: We systematically searched through EMBASE. The retrieved articles were supplemented by articles containing relevant data or provided important background information. Studies that were included investigated the value and/or usability of diagnostic tests for tremor. Results: In most patients, history and clinical examination by an experienced movement disorders neurologist are sufficient to establish a correct diagnosis, and further ancillary examinations will not be needed. Ancillary investigation should always be guided by tremor type(s) present and other associated signs and symptoms. The main ancillary examination techniques currently are electromyography and SPECT imaging. Unfortunately, many techniques have not been studied in large prospective, diagnostic studies to be able to determine important variables like sensitivity and specificity. Conclusion: When encountering a patient with tremor, history, and careful clinical examination should guide the diagnostic process. Adherence to the diagnostic work-up provided in this review will help the diagnostic process of these patients.

Background: Tremor is the most prevalent movement disorder in clinical practice. It is defined as involuntary, rhythmic, oscillatory movements. The diagnostic process of patients with tremor can be laborious and challenging, and a clear, systematic overview of available diagnostic techniques is lacking. Tremor can be a symptom of many diseases, but can also represent a distinct disease entity. Objective: The objective of this review is to give a clear, systematic and step-wise overview of the diagnostic work-up of a patient with tremor. The clinical relevance and value of available laboratory tests in patients with tremor will be explored. Methods: We systematically searched through EMBASE. The retrieved articles were supplemented by articles containing relevant data or provided important background information. Studies that were included investigated the value and/or usability of diagnostic tests for tremor. Results: In most patients, history and clinical examination by an experienced movement disorders neurologist are sufficient to establish a correct diagnosis, and further ancillary examinations will not be needed. Ancillary investigation should always be guided by tremor type(s) present and other associated signs and symptoms. The main ancillary examination techniques currently are electromyography and SPECT imaging. Unfortunately, many techniques have not been studied in large prospective, diagnostic studies to be able to determine important variables like sensitivity and specificity. Conclusion: When encountering a patient with tremor, history, and careful clinical examination should guide the diagnostic process. Adherence to the diagnostic work-up provided in this review will help the diagnostic process of these patients.

How to Tackle Tremor – Systematic Review of the Literature and Diagnostic Work-Up

Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL-related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is β2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment.

Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL-related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is &#x3b2;2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment.