Emerging therapies for childhood-onset movement disorders.

PURPOSE OF REVIEW: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). RECENT FINDINGS: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. SUMMARY: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

Paraneoplastic movement disorders.

Paraneoplastic movement disorders are diverse autoimmune neurological illnesses occurring in the context of systemic cancer, either in isolation or as part of a multifocal neurological disease. Movement phenomena may be ataxic, hypokinetic (parkinsonian), or hyperkinetic (myoclonus, chorea, or other dyskinetic disorders). Some disorders mimic neurodegenerative or hereditary illnesses. The subacute onset and coexisting nonclassic features of paraneoplastic disorders aid distinction. Paraneoplastic autoantibodies provide further information regarding differentiating cancer association, disease course, and treatment responses. A woman with cerebellar ataxia could have metabotropic glutamate receptor 1 autoimmunity, in the setting of Hodgkin lymphoma, a mild neurological phenotype and response to immunotherapy. A different woman, also with cerebellar ataxia, could have Purkinje cytoplasmic antibody type 1 (anti-Yo), accompanying ovarian adenocarcinoma, a rapidly progressive phenotype and persistent disabling deficits despite immune therapy. The list of antibody biomarkers is growing year-on-year, each with its own ideal specimen type for detection (serum or CSF), accompanying neurological manifestations, cancer association, treatment response, and prognosis. Therefore, a profile-based approach to screening both serum and CSF is recommended. Immune therapy trials are generally undertaken, and include one or more of corticosteroids, IVIg, plasma exchange, rituximab, or cyclophosphamide. Symptomatic therapies can also be employed for hyperkinetic disorders.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

[Drug-induced movement disorders : nosology and treatment]. / Mouvements anormaux iatrogènes : aspects nosologiques et thérapeutiques.

Movements disorders are frequently encountered in general practice and emergency departments and are in many cases of iatrogenic origin. Dopamine D2 receptor blocking agents (DRBA), mainly neuroleptics, are most often incriminated. These drug-induced movement disorders (DIMD) can be classified according to the kinetics of the manifestations (acute DIMD and tardive syndromes), the phenomenology of the abnormal movements observed or depending on the pharmacological agent involved. The diagnosis is based on the time course of the events, clinical examination and meticulous anamnesis of the patient's previous and current treatments. Management is always based on the interruption of the suspected causal treatment when possible. Some cases have a severe prognosis and require immediate treatment.

Les mouvements anormaux sont fréquemment rencontrés en médecine générale et aux urgences et sont, dans de nombreux cas, d'origine iatrogène. Les molécules les plus souvent incriminées sont les agents bloqueurs des récepteurs dopaminergiques D2 (DRBA) et principalement les neuroleptiques. Ces mouvements anormaux iatrogènes (MAI) peuvent être classés selon la cinétique des manifestations (MAI aigus et syndromes tardifs), la sémiologie des mouvements observés, ou encore, selon l'agent pharmacologique en cause. Le diagnostic repose sur le décours temporel des manifestations, l'examen clinique et une anamnèse fouillée des traitements antérieurs et actuels du patient. La prise en charge repose toujours sur l'arrêt du traitement causal quand cela est possible. Il existe des situations urgentes grevées d'un pronostic sévère et redevables d'un traitement rapide.

Deep brain stimulation for movement disorders treatment in Africa: The current status, outcomes, and challenges.

Movement disorders (MDs), a diverse group of neurological conditions characterized by abnormal and involuntary movements, have a profound impact on individuals, families, and healthcare systems. Deep Brain Stimulation (DBS) has emerged as a promising therapeutic intervention, offering relief from symptoms and improved quality of life. By implanting electrodes in specific brain regions and connecting them to a pulse generator, DBS modulates aberrant neural activity underlying these disorders. While DBS has gained recognition globally, its utilization in African countries remains limited. This comprehensive article presents the results of a literature review on the status of DBS therapy for MDs in Africa. The review assesses treatment outcomes, patient demographics, and challenges tied to implementing DBS in the African context. The findings reveal promising developments in DBS therapy across several African countries, particularly in treating Parkinson's disease and dystonia. However, challenges related to awareness, access to specialized care, and a scarcity of expertise still impede broader adoption. The article underscores the urgent need for collaborative efforts, policy changes, and increased training to expand the reach of DBS therapy, thus mitigating the burden of MDs on the African continent.

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders.

OBJECTIVE: This article reviews common sleep-related movement disorders, including their clinical description, epidemiology, pathophysiology (if known), and evaluation and management strategies. This article will provide the reader with a good foundation for approaching concerns that are suggestive of sleep-related movement disorders to properly evaluate and manage these conditions. LATEST DEVELOPMENTS: α2δ Ligands, such as gabapentin enacarbil, can be used for the initial treatment of restless legs syndrome (RLS) or in those who cannot tolerate, or have developed augmentation to, dopamine agonists. Another option is the rotigotine patch, which has a 24-hour treatment window and may be beneficial for those who have developed augmentation with short-acting dopamine agonists. IV iron can improve RLS symptoms even in those whose serum ferritin level is between 75 ng/mL and 100 ng/mL. At serum ferritin levels greater than 75 ng/mL, oral iron will likely have minimal absorption or little effect on the improvement of RLS. Research has found an association between RLS and cardiovascular disease, particularly in people who have periodic limb movements of sleep. ESSENTIAL POINTS: RLS is the most common sleep-related movement disorder. Its pathophysiology is likely a combination of central iron deficiency, dopamine overproduction, and possibly cortical excitation. Treatment includes oral or IV iron. Dopaminergic medications can be very effective but often lead to augmentation, which limits their long-term use. Other sleep-related movement disorders to be aware of are sleep-related rhythmic movement disorder, nocturnal muscle cramps, sleep-related propriospinal myoclonus, sleep bruxism, and benign myoclonus of infancy.

Spasticity and movement disorders in cerebral palsy.

PURPOSE: To review the neurosurgical treatments of children with movement disorders associated with cerebral palsy (CP) during the previous decades, up to the present day. METHODS: An extensive literature review was undertaken to identify important publications about this subject. My experience treating children with these disorders over the past three decades was included in the individual sections. RESULTS: Peripheral neurotomies have been developed for children with focal spasticity. For those with spastic paraparesis, selective lumbar rhizotomies were developed, and for those with spastic quadriparesis, intrathecal baclofen infusions were developed. Both effectively alleviate spasticity in the affected extremities. Generalized dystonia associated with CP has been treated with deep brain stimulation with mild improvement, but treatment with intrathecal baclofen and intraventricular baclofen improve those movements markedly. No effective treatment has been reported for children with athetoid CP. For those with choreiform CP, deep brain stimulation may be effective but intrathecal baclofen does not appear to be. CONCLUSION: Treatment of children with movement disorders associated with CP increased slowly in the 1970s and 1980s but accelerated rapidly in the 1990s with the introduction of lumbar dorsal rhizotomies and intrathecal baclofen. In the last 30 years, tens of thousands of children with spasticity and movement disorders associated with CP have been treated by pediatric neurosurgeons, and their care has become an integral component of current pediatric neurosurgical practice.

Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.

Deep Brain Stimulation for the Treatment of Hemichorea: Case Series and Literature Review.

Background: Hemichorea (HC) and its severe form hemiballismus (HB) are rare movement disorders which can be medically refractory to treatments and may need surgical intervention. Case Report: We report 3 patients with HC-HB who had meaningful clinical improvement with unilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi). We identified 8 prior cases of HC-HB treated with GPi-DBS, and a majority of these patients experienced significant improvement in their symptoms. Discussion: GPi-DBS can be considered in medically refractory HC-HB in carefully selected patients. However, data is limited to small case series and further studies are needed.

Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

[Functional neurological disorders: gait and movement disorders]. / Troubles neurologiques fonctionnels : marche et mouvements anormaux.

Functional neurological disorders consist of a group of neurological symptoms and syndromes for which a known "organic" cause cannot be identified. They still represent one of the most difficult diagnostic challenge for the neurologist, who can only rely on clinical criteria. Functional gait and movement disorders represent an important subgroup of these conditions and a frequent reason for consultation. The neurobiological basis of these manifestations remains poorly understood despite the progress of functional neuroimaging. Beyond the diagnosis process, its communication to the patient and its meaning represent another challenge, which requires tactful explanations as a prerequisite to a successful management.

Les troubles neurologiques fonctionnels constituent un ensemble de symptômes et syndromes neurologiques dont une cause «organique¼ ne peut être démontrée. Ils représentent toujours actuellement un des défis diagnostiques le plus difficile pour le neurologue dès lors qu'il ne peut s'appuyer que sur des critères cliniques. Les troubles de la marche et les mouvements anormaux fonctionnels constituent un sous-groupe significatif de ces affections et un motif fréquent de consultation. Les bases neurobiologiques de ces manifestations demeurent largement incomprises en dépit des progrès de la neuroimagerie fonctionnelle. Au-delà du processus diagnostique, l'annonce au patient du diagnostic et de sa signification impose une expertise et un soin particulier parce que participant à la démarche thérapeutique.

Hyperkinetic movement disorders following SARS-CoV-2 infection and vaccination - an update.

The aim of this review was to summarise current knowledge regarding hyperkinetic movement disorders related to SARS-CoV-2 infection and vaccination in terms of phenomenology, epidemiology, pathogenesis and treatment. After a thorough review of the PubMed and Google Scholar databases (2020-2022), we identified myoclonus and ataxia sometimes accompanied by opsoclonus (AMS) as the two most frequent COVID-19 sequelae, with chorea, tremor and dystonia being very rare. The pathogenesis seems to be variable, but in the majority of AMS cases it was autoimmunological, with good response and recovery after corticosteroids or intravenous immunoglobulins infusions. Vaccination may be complicated by hyperkinetic movement disorders (e.g. tremor, dystonia), but this is very rare. Patients with Deep Brain Simulation depletion should not be postponed due to lockdowns as this may result in fatal outcomes.

Cerebellar deep brain stimulation for the treatment of movement disorders in cerebral palsy.

OBJECTIVE: Cerebral palsy (CP) represents the most common childhood physical disability that encompasses disorders of movement and posture attributed to nonprogressive disturbances that occurred in the developmental fetal or infant brain. Dyskinetic CP (DCP), the second most common type of CP after spastic forms, refers to a subset of patients in whom dystonia and choreoathetosis are the predominant motor manifestations. Most children with CP have abnormal brain MRI studies indicative of cortical and deep gray matter damage consistent with hypoxic ischemic encephalopathy, which may preclude or suggest decreased efficacy of standard deep brain stimulation (DBS) targets. The cerebellum has been posited as an attractive target for treatment of DCP because it is frequently spared from hypoxic ischemic damage and has shown promise in alleviating patient symptoms both in early work in the 1970s and in more recent case series with DBS. METHODS: The authors performed bilateral cerebellar DBS implantation, targeting the dentate nucleus (DN) and cerebellar outflow pathway, in 3 patients with DCP. Leads were connected to a pulse generator that senses local field potentials during chronic continuous DBS. The authors report their surgical methods, examples of chronic cerebellar local field potential recordings, and preliminary clinical outcomes. Motor outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Three patients 14-22 years old with DCP and MRI evidence of structural damage to the basal ganglia were offered cerebellar stimulation targeting the DN. All patients tolerated the procedure well and demonstrated improvement in subjective motor function as well as objective improvement in the Burke-Fahn-Marsden Dystonia Rating Scale movement subscale, although the range of responses was variable (19%-40%). Patients experienced subjective improvement in motor function including ease of hand movements and coordination, gait, head control, speech, decreased overflow, and diminished muscle tightness. CONCLUSIONS: DBS of the dentate nuclei in patients with DCP appears to be safe and shows preliminary evidence of clinical benefit. New chronic sensing technology may allow for determination of in vivo mechanisms of network disruption in DCP and allow for further understanding of the effects of neuromodulation on brain physiology. Larger studies with long-term follow up will be required to further elucidate the clinical benefits of this therapy. This report addresses a gap in the literature regarding the technical approach to image-based stereotactic targeting and chronic neural recording in the DN.

Movement disorders: is the Feldenkrais method effective? IQWiG Reports - Commission

The Feldenkrais method is presumably preferred by social groups who generally strive to use non-drug and non-surgical interventions for preventing and treating diseases. Since chronic pain is more common in advanced age, older people are likely to be more interested in this method. This health technology assessment (HTA) report investigates the use of the Feldenkrais method as a therapeutic intervention, i.e. only in people with movement disorders, rather than for preventive purposes or in persons with mobility impairments which are not defined in more detail. Demand is nurtured, in part, by the Feldenkrais method being expected to favourably affect private and social life due to greater self-perceived physical mobility. Since the Feldenkrais method's trademark protection is viewed positively, these groups may harbour erroneous assumptions with regard to the benefits to be expected. From an ethical perspective, this tends to be viewed critically because users who do not reap any benefit may have incurred costs to be paid out of pocket (the relevance of this aspect differs between social groups) and not utilized effective therapies. A total of 6 randomized controlled trials (RCTs), all with a high risk of bias, were identified for 5 therapeutic indications, and hints of (greater) benefit were determined for 2 therapeutic indications. For patients with Parkinson's disease, there is a hint of greater benefit of the Feldenkrais method in comparison with the passive strategy of an educational programme in the form of lectures. This benefit consists of improved mobility and health-related quality of life at the end of treatment. In the comparison with active strategies, the available evidence for patients with chronic low back pain is inconsistent. Compared with an educational programme involving trunk stabilization exercises, there is a hint of greater benefit of the Feldenkrais method with regard to improved mobility and health-related quality of life at the end of the 5-week treatment period. In comparison with back school, there is a hint of greater benefit of the Feldenkrais method with regard to pain reduction, but also a hint of lesser benefit of this method with regard to health-related quality of life after 3 months. However, no differences in effects were found directly at the end of therapy. There is no hint of either long-term benefit of the Feldenkrais method or for its benefit in other therapeutic indications. It was also impossible to derive any hint of harm from the Feldenkrais method, with the studies failing to provide data on deaths and adverse events. The question about the benefit of the Feldenkrais method in comparison with active strategies such as extensive physiotherapy generally remains open. The determined evidence is based on group interventions in the "Awareness Through Movement" (ATM) format rather than one-on-one interventions in the "Functional Integration" format (only 4 sessions investigated in 1 study). The intervention costs equal €10 to €20 per person and group session or €60 to €90 per one-on-one session. These costs are typically to be paid out of pocket by patients, a fact which is of differing relevance for different social groups. No studies on health economic aspects are available. If greater benefit were to be confirmed for certain therapeutic indications, some problematic issues might arise from an ethical or organizational perspective, particularly in view of limited access to the method. Since liability issues are conceivable in case of demonstrable physical injuries, the use of the Feldenkrais method as a therapeutic intervention would require corresponding basic medical qualifications of Feldenkrais teachers, possibly with state accreditation. From a social and organizational perspective, use of the Feldenkrais method requires some patient collaboration (to ensure continuity of the intervention) and potentially leads to lower utilization of medically trained healthcare providers. If the costs of the Feldenkrais method were to be covered by statutory health insurance for therapeutic indications with established benefit, the service would need to be offered nationwide by appropriately trained personnel. Additional resources would likely be needed. Overall, little evidence is available. From an ethical perspective, the absence of evidence from RCTs is problematic for informed decision making but does not constitute evidence of an absent benefit. Only 2 small, ongoing RCTs of questionable relevance were identified, and therefore, the availability of evidence is not expected to change in the short term. Due to the limited availability of data, further research is needed, particularly regarding long-term effects of the Feldenkrais method, its application in various therapeutic indications, and in comparison with further active comparator therapies typically used in practice, e.g. physiotherapy.

Elective and Emergency Deep Brain Stimulation in Refractory Pediatric Monogenetic Movement Disorders Presenting with Dystonia: Current Practice Illustrated by Two Cases.

BACKGROUND: Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal posturing and twisting movements. In pediatric patients, dystonia often negatively influences quality of life. Pharmacological treatment for dystonia is often inadequate and causes adverse effects. Deep brain stimulation (DBS) appears to be a valid therapeutic option for pharmacoresistant dystonia in children. METHODS: To illustrate the current clinical practice, we hereby describe two pediatric cases of monogenetic movement disorders presenting with dystonia and treated with DBS. We provide a literature review of similar previously described cases and on different clinical aspects of DBS in pediatric dystonia. RESULTS: The first patient, a 6-year-old girl with severe dystonia, chorea, and myoclonus due to an ADCY5 gene mutation, received DBS in an elective setting. The second patient, an 8-year-old boy with GNAO1-related dystonia and chorea, underwent emergency DBS due to a pharmacoresistant status dystonicus. A significant amelioration of motor symptoms (65% on the Burke-Fahn-Marsden Dystonia Rating Scale) was observed postoperatively in the first patient and her personal therapeutic goals were achieved. DBS was previously reported in five patients with ADCY5-related movement disorders, of which three showed objective improvement. Emergency DBS in our second patient resulted in the successful termination of his GNAO1-related status dystonicus, this being the eighth case reported in the literature. CONCLUSION: DBS can be effective in monogenetic pediatric dystonia and should be considered early in the disease course. To better evaluate the effects of DBS on patients' functioning, patient-centered therapeutic goals should be discussed in a multidisciplinary approach.

[Functional (Psychogenic) Movement Disorder Focusing on Involuntary Movements: A Review].

Functional neurological disorders differ from malingering/factitious disorders and are diagnosed based solely on careful history taking and neurological evaluation. Some clinical characteristics, including distractibility, entrainability, and variability are important to identify the positive physical signs that indicate functional alterations. Thorough investigations are not essential to exclude organic pathologies, whereas electrophysiological and radiological findings are sometimes useful. Neurologists play an important role when they explain the diagnosis to the patient. The explanation itself may be therapeutic, when delivered successfully and may help patients to understand the nature and mechanisms underlying their movement disorder. A multidisciplinary team approach, including coordination between rehabilitation therapists and psychotherapists may produce positive treatment outcomes, particularly in movement disorder centers. In this article, we discuss some functional neurological disorders, including those in patients with functional movement disorders (involuntary movements) together with video presentations.