Distinctive Movement Disorder Research Articles

Effect of Pathogenic Mutations on the Formation of High-Order Dynamin 2 Assemblies in Living Cells.

Mutations in dynamin 2 (DNM2) have been associated with two distinct movement disorders: Charcot-Marie-Tooth neuropathies (CMT) and centronuclear myopathy (CNM). Most of these mutations are clustered in the pleckstrin homology domain (PHD), which engages in intramolecular interactions that limit dynamin self-assembly and GTPase activation. CNM mutations interfere with these intramolecular interactions and suppress the formation of the autoinhibited state. CMT mutations are located primarily on the opposite surface of the PHD, which is specialized for phosphoinositide binding. It has been speculated that the distinct locations and interactions of residues mutated in CMT and CNM explain why each set of mutations causes either one disease or the other, despite their close proximity within the PHD sequence. We previously reported that at least one CMT-causing mutant, lacking residues 555DEE557 (ΔDEE), displays the same inability to undergo autoinhibition as observed in CNM-linked mutants. Here, we show that both the DNM2ΔDEE and CNM-linked DNM2A618T mutants form larger and more stable structures on the plasma membrane than that of wild-type DNM2 (DNM2WT). However, DNM2A618T forms cytoplasmic inclusions at concentrations lower than those of either DNM2WT or DNM2ΔDEE, suggesting that CNM-linked mutations confer more severe gain-of-function properties than the ΔDEE mutation.

Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy.

Neuronal ceroid lipofuscinosis type 2 (CLN2-disease) is an inherited childhood-onset neurodegenerative condition, with classical early features of speech delay, epilepsy, myoclonus, ataxia, and motor regression. This study aimed to better characterize the spectrum of movement disorders in CLN2-disease in a cohort of children receiving enzyme replacement therapy (ERT). A cohort of 18 children attending a single center for treatment with cerliponase alfa ERT was systematically assessed using a standardized structured history and a double-scored, video-recorded examination using the Unified Batten Disease Rating Scale (UBDRS) and Abnormal Involuntary Movement Scale. Noncanonical movement disorders are common: while ataxia (89%) and myoclonus (83%) were near-universal, spasticity and dystonia were experienced by over half (61% each), with children having a median of 4 distinct movement disorder phenotypes. This progression was stereotyped with initial ataxia/myoclonus, then hyperkinesia/spasticity, and later hypokinesia. ERT slows progression of movement disorders, as measured by the UBDRS physical subscale, with 1.45 points-per-month progression before diagnosis and 0.44 points-per-month while on treatment (p = 0.019). Movement disorders are a core feature of CLN2-disease and follow a typical pattern of progression which is slowed by ERT. Identifying and treating movement disorders should become standard, especially given increased patient survival.

Emerging Subspecialties: Pediatric Movement Disorders Neurology.

Pediatric movement disorders (PMD) neurologists care for infants, children, and adolescents with conditions that disrupt typical movement; serving as important subspecialist child neurologists in both academic and private practice settings. In contrast to adult movement disorders neurologists whose "bread and butter" is hypokinetic Parkinson disease, PMD subspecialty practice is often dominated by hyperkinetic movement disorders including tics, dystonia, chorea, tremor, and myoclonus. PMD neurology practice intersects with a variety of subspecialties, including neonatology, developmental pediatrics, rehabilitation medicine, epilepsy, child & adolescent psychiatry, psychology, orthopedics, genetics & metabolism, and neurosurgery. Over the past several decades, significant advancements in the PMD field have included operationalizing definitions for distinct movement disorders, recognizing the spectrum of clinical phenotypes, expanding research on genetic and neuroimmunologic causes of movement disorders, and advancing available treatments. Subspecialty training in PMD provides trainees with advanced clinical, diagnostic, procedural, and management skills that reflect the complexities of contemporary practice. The child neurologist who is fascinated by the intricacies of child motor development, appreciates the power of observation skills coupled with a thoughtful physical examination, and is excited by the challenge of the unknown may be well-suited to a career as a PMD specialist.

Bradykinesia and dystonia

Background: Bradykinesia has been reported in patients with dystonia. Despite this, the pathophysiological mechanisms of bradykinesia in dystonia remain largely unknown.Methods: We here performed a comprehensive literature search and reviewed clinical and experimental studies on bradykinesia in patients with dystonia.Results: Many studies have documented the presence of bradykinesia in patients with idiopathic and inherited isolated dystonia, regardless of the presence of parkinsonism. In addition, bradykinesia has been observed as a side effect in dystonic patients who have undergone deep brain stimulation, in those with functional dystonia as well as in those with combined dystonia, e.g., dystonia-parkinsonism. These clinical and experimental findings support the hypothesis that dysfunction in a brain network involving the basal ganglia, primary sensorimotor cortex, and cerebellum may play a key role in the pathophysiology of both bradykinesia and dystonia.Conclusion: Bradykinesia is frequently observed in dystonia. We may gain insights into the pathophysiological underpinnings of two distinct movement disorders by investigating this issue. Furthermore, a deeper understanding of bradykinesia in dystonia may have terminological implications in this field.

Movement disorders associated with neuronal antibodies.

Movement disorders are one of the common clinical features of neurological disease associated with neuronal antibodies which is a group of potentially reversible disorder. They can present with hypokinetic or hyperkinetic types of involuntary movements and may have other associated neurological symptoms. The spectrum of abnormal movements associated with neuronal antibodies is widening. Some specific phenomenology of movement disorders are likely to give clue about the type of antibody, for instance, presence of paroxysmal dystonia (facio-brachial dystonic seizures) are a pointer toward presence of LGI-1 antibodies, and orofacial lingual dyskinesia is associated with NMDAR associated encephalitis. The presence of specific type of movement disorder allows high suspicion of testing of certain specific type of antibodies. In this review, we have discussed the various antibodies and the spectrum of movement disorder associated with them, highlighting if any distinct movement disorder allows the clinician to suspect type of antibody in a certain clinical context. We have also reviewed the treatment of the movement disorder associated with the neuronal antibodies. Physicians should have high index of suspicion of these disorders, as early institution of treatment options can lead to better outcome.

Grey matter abnormalities in methcathinone abusers with a Parkinsonian syndrome.

BackgroundA permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1‐weighted MRI.MethodsWe have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1‐weighted structural and resting‐state functional MRI.ResultsSegmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel‐based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface‐based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto‐occipital, and temporal regions. Resting‐state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex.ConclusionTaken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1‐weighted structural MRI.

Management of drug-induced movement disorders in psychiatry: an update

Drug-induced movement disorders (DIMD) represent a variety of iatrogenic and clinically distinct movement disorders, including akathisia, tardive dyskinesia, dystonia, and Parkinsonism. DIMD remain a significant burden especially among certain patient populations receiving psychotropic medication. Knowledge of DIMDs will allow clinicians and healthcare professionals to better identify and manage patients with these conditions. Here we discuss the important features and current practical management steps of different types of DIMD in psychiatry.

Bulbar and Limb Myorhythmia with “Smooch Sign”: A Distinctive Movement Disorder in an Adult Patient with Reversible Anti-NMDA Receptor Encephalitis Associated with an Ovarian Teratoma

Anti-N-Methyl-D-Aspartate receptor encephalitis is a recently described entity (Dalmau et al. 2007, 2008) that may present with a variety of complex movements in addition to other features (Kleinig et al. 2008). The purpose of our presentation of such a patient is twofold: (1) to characterize these complex oculo-oro-linguo-masticatory and limb movements with “smooch sign” as myorhythmia, based on a combined clinical and electrophysiological analysis (Masucci et al. 1984); and (2) to document possibly characteristic EEG evolution in the course of observation in our institution for three weeks from diffuse slowing to evolving rhythmic delta activity, which may represent a pattern of electrographic seizure activity.

Patient-reported Needs, Non-motor Symptoms, and Quality of Life in Essential Tremor and Parkinson's Disease.

BackgroundNon-motor symptoms, quality of life, service needs, and barriers to care of individuals with movement disorders are not well explored. This study assessed these domains within a sample of individuals with essential tremor (ET) and Parkinson's disease (PD).MethodsA survey exploring symptoms, needs, and barriers to care was disseminated to a convenience sample (N = 96) of individuals with a primary diagnosis of ET (N = 19) or PD (N = 77).ResultsSimilarities in overall quality of life and impact on daily functioning were found across individuals with ET and PD. Noteworthy differences included endorsement of different types of service needs and utilization patterns and fewer non-motor symptoms reported among those with ET (M = 6.1, SD = 2.4) than those with PD (M = 10.4, SD = 3.4). Non-motor symptoms significantly impacted movement disorder-related quality of life for both diagnostic groups, but this relationship was stronger for individuals with ET, t(12) = 3.69, p = 0.003, β = 0.73 than with PD, t(56) = 4.00, p<0.001, β = 0.47. Individuals with ET also reported higher rates of stigma (31.6% vs. 7.8%) and greater impact of non-motor symptoms on emotional well-being, R2 = 0.37, F(1, 13) = 7.17, p = 0.020.DiscussionThis is the first study to describe and compare the needs, barriers to care, and impact on quality of life of two distinct movement disorder groups. Our results support the recent efforts of the field to identify interventions to address the non-motor symptoms of movement disorders and indicate need for greater appreciation of the specific differences in symptoms and quality of life experienced across movement disorder diagnoses.

Patient-reported Needs, Non-motor Symptoms, and Quality of Life in Essential Tremor and Parkinson’s Disease

<strong>Background:</strong> Non-motor symptoms, quality of life, service needs, and barriers to care of individuals with movement disorders are not well explored. This study assessed these domains within a sample of individuals with essential tremor (ET) and Parkinson’s disease (PD). <strong>Methods:</strong> A survey exploring symptoms, needs, and barriers to care was disseminated to a convenience sample (<em>N</em>=96) of individuals with a primary diagnosis of ET (<em>N</em>=19) or PD (<em>N</em>=77). <strong>Results:</strong> Similarities in overall quality of life and impact on daily functioning were found across individuals with ET and PD. Noteworthy differences included endorsement of different types of service needs and utilization patterns and fewer non-motor symptoms reported among those with ET (M=6.1, SD=2.4) than those with PD (<em>M</em>=10.4, SD=3.4). Non-motor symptoms significantly impacted movement disorder-related quality of life for both diagnostic groups, but this relationship was stronger for individuals with ET, <em>t</em>(12)=3.69, <em>p</em>=0.003, <em>β</em>=0.73 than with PD, <em>t</em>(56)=4.00, <em>p</em>&lt;0.001, <em>β</em>=0.47. Individuals with ET also reported higher rates of stigma (31.6% vs. 7.8%) and greater impact of non-motor symptoms on emotional well-being, <em>R</em>²=0.37, <em>F</em>(1, 13)=7.17, <em>p</em>=0.020. <strong>Discussion:</strong> This is the first study to describe and compare the needs, barriers to care, and impact on quality of life of two distinct movement disorder groups. Our results support the recent efforts of the field to identify interventions to address the non-motor symptoms of movement disorders and indicate need for greater appreciation of the specific differences in symptoms and quality of life experienced across movement disorder diagnoses.

Holmes' and palatal tremor following brainstem haemorrhage

Holmes' tremor is a rare symptomatic movement disorder characterised by resting tremor, enhanced by posture and further exacerbated by kinetic action. Palatal tremor is a distinct movement disorder characterised by rhythmic palatal contractions. Hypertrophic olivary degeneration (HOD) is a rare trans-synaptic degeneration that results from injury to the Guillain–Mollaret triangle [1]. Co-existence of Holmes' and palatal tremor is rare. We herein present a patient who developed a combination of Holmes' and palatal tremor in association with HOD, 6 months following brainstem haemorrhage.

Anti-NMDA-receptor encephalitis presenting as postpartum psychosis in a young woman, treated with rituximab

A severe paraneoplastic form of acute encephalitis associated with antibodies against the N-methyl D-aspartate (NMDA) receptor typically occurs in young individuals and is associated, but not always, with an underlying tumor. If diagnosed early, initiation of immunotherapy and tumor removal (if present) may result in recovery. We report a case in a 25-year-old young woman who presented to our medical center with postpartum psychosis. Treatment with rituximab (a chimeric monoclonal antibody against the protein CD20) resulted in gradual improvement in mental status and resolution of seizure activity episodes. A year after diagnosis and treatment, the patient was doing well without recurrences, and no tumors appeared. This is the first described case of anti–NMDA-receptor antibodies encephalitis that presented initially as a postpartum psychosis disorder and was successfully treated with rituximab.

The distinct movement disorder in anti‐NMDA receptor encephalitis may be related to status dissociatus: A hypothesis

The majority of patients with anti-N-methyl-D-aspartate-receptor encephalitis (NMDAE) present a characteristic movement disorder, which consists of complex bilateral stereotyped movements of the arms, with perioral and eye movements, and less frequently involvement of the legs. We have observed striking similarities in the characteristics of the abnormal movements observed in NMDAE and those described in Status Dissociatus, which is characterized by a complete breakdown of state-determining boundaries (wakefulness, REM and NREM sleep) and can result from pathophysiologically diverse disorders (e.g. fatal familial insomnia, delirium tremens, Morvan's syndrome). Here, we suggest that the state of paradoxical responsiveness in which NMDAE patients present these stereotyped movements may be that of Status Dissociatus and discuss the clinical similarities and pathophysiological explanations that support such a suggestion. This hypothesis explains why patients that seem to be unconscious have a movement disorder that is not epileptic and may have management implications, since many patients with NMDAE-related movement disorder are treated with anticonvulsants that may not be indicated.

Sonographic Alteration of Lenticular Nucleus in Focal Task-Specific Dystonia of Musicians

Background/Aims: In distinct movement disorders, transcranial sonography detects alterations of deep brain structures with higher sensitivity than other neuroimaging methods. Lenticular nucleus hyperechogenicity on transcranial sonography, thought to be caused by increased local copper content, has been reported as a characteristic finding in primary spontaneous dystonia. Here, we wanted to find out whether deep brain structures are altered in task-specific dystonia. Methods: The frequency of sonographic brainstem and basal ganglia changes was studied in an investigator-blinded setting in 15 musicians with focal task-specific hand dystonia, 15 musicians without dystonia, and 15 age- and sex-matched nonmusicians without dystonia. Results: Lenticular nucleus hyperechogenicity was found in 12 musicians with task-specific dystonia, but only in 3 nondystonic musicians (Fisher’s exact test, p = 0.001) and 2 nonmusicians (p < 0.001). The degree of lenticular nucleus hyperechogenicity in affected musicians correlated with age, but not with duration of music practice or duration of dystonia. In 2 of 3 affected musicians with normal echogenic lenticular nucleus, substantia nigra hyperechogenicity was found. Conclusions: Our findings support the idea of a pathogenetic link between primary spontaneous and task-specific dystonia. Sonographic basal ganglia alteration might indicate a risk factor that in combination with extensive fine motor training promotes the manifestation of task-specific dystonia.

Substantia nigra hyperechogenicity is a risk marker of Parkinson’s disease: no

During the past two decades, transcranial sonography (TCS) has developed to an increasingly used brain imaging method that visualizes characteristic patterns of basal ganglia alterations in distinct movement disorders. Since the discovery of a characteristic abnormal hyperechogenic appearance of substantia nigra (SN) on TCS in Parkinson's disease (PD), which is stable during the course of the disease and probably present already in preclinical disease stages, the results of several studies have promoted the idea that this TCS finding in healthy subjects might be a risk marker of PD. The present view summarizes current scientific evidence favouring the idea that the TCS finding of SN hyperechogenicity alone may not be a (strong) risk marker of PD. Especially, it is discussed how reliable this TCS finding is, whether this TCS finding can be regarded as a progression marker or a risk marker of PD, how strongly it may indicate a risk of PD, what else if not an increased risk of PD could be indicated, and which role TCS of SN may finally play in the detection of subjects at risk of PD.

The distinctive movement disorder of ovarian teratoma‐associated encephalitis

The movement disorder observed in four cases of ovarian teratoma associated encephalitis is described. The illness began with neuropsychiatric symptoms and was followed by prolonged unresponsiveness, respiratory failure, and autonomic instability. The movement disorder consisted of semirhythmic repetitive bulbar and limb movements and persisted during prolonged periods of unresponsiveness, diminishing as awareness returned. The characteristics of the movement disorder differed from recognized dyskinesias. It is suggested that interruption of forebrain corticostriatal inputs by anti-N-methyl-D-aspartate (NMDA) receptor antibodies removes tonic inhibition of brainstem pattern generators releasing primitive patterns of bulbar and limb movement. Recognition of the distinctive movements should prompt a search for an ovarian teratoma since the condition is responsive to tumor resection and immunomodulation.

Oculomasticatory myorhythrma: A unique movement disorder occurring in Whipple's disease

We describe two patients and a previously reported patient who acquired unique pendular vergence oscillations of the eyes and concurrent contractions of the masticatory muscles, i.e., oculomasticatory myorhythmia (OMM). The smooth disjunctive eye movements cycled with a frequency of 0.8 to 1.2 Hz. An analysis of peak velocities (15 to 200 degrees/sec) with respect to peak amplitudes (5 to 25 degrees) revealed dynamics characteristic of normal vergence movements. The pathological alterations resulting in pendular vergence oscillations implicate a separately functioning, physiologically normal vergence system within the brainstem. In addition to paralysis of vertical gaze, each patient also experienced progressive somnolence and intellectual deterioration. An intestinal biopsy in 1 patient established a diagnosis of Whipple's disease, which led to appropriate treatment and amelioration of the OMM. A pathological diagnosis of Whipple's disease of the central nervous system was made in the other 2 patients; results of an intestinal biopsy in one of these patients were normal. No patient had palatal myoclonus, and olivary pseudohypertrophy was not found in two autopsy examinations. Thus, OMM is a distinct movement disorder and has been recognized only in Whipple's disease. We conclude that patients with OMM should be treated presumptively for Whipple's disease of the central nervous system, even if a jejunal biopsy is normal.

Clinical spectrum of ocular bobbing.

Ocular bobbing is a distinctive movement disorder occurring in a variety of related forms herein classified as `typical', `monocular', and `atypical'. `Typical' ocular bobbing occurs in patients with paralysis of horizontal conjugate eye movements and consists of abrupt, spontaneous downward jerks of the eyes with a slow return to the mid position. The `monocular' type reflects co-existing unilateral third nerve paresis in addition to the bobbing. The `atypical' type includes either a variation unexplained by associated oculomotor palsy, or bobbing with intact spontaneous or reflex horizontal eye movements. The clinical spectrum of ocular bobbing, its varied causes, and its prognostic significance are exemplified in a report of nine cases.