Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

Canine paroxysmal dyskinesia-a review.

Paroxysmal dyskinesias (PDs) are a group of involuntary, hyperkinetic movement disorders that recur episodically and may last seconds to hours. An important feature of PD is that there is no loss of consciousness during the episode. Using a clinical classification, three main types of PDs have been distinguished in canine PD: (1) paroxysmal kinesigenic dyskinesia (PKD) that commences after (sudden) movements, (2) paroxysmal non-kinesigenic dyskinesia (PNKD) not associated with exercise and can occur at rest, and (3) paroxysmal exertion-induced dyskinesia (PED) associated with fatigue. Canine PDs are diagnosed based on the clinical presentation, history, and phenomenology. For the latter, a video recording of the paroxysmal event is extremely useful. An etiological classification of canine PDs includes genetic (proven and suspected), reactive (drug-induced, toxic, metabolic, and dietary), structural (neoplasia, inflammatory, and other structural causes), and unknown causes. In this review, an overview of all reported canine PDs is provided with emphasis on phenotype, genotype, and, where possible, pathophysiology and treatment for each reported canine PD.

Neuron specific quantitation of Gαolf expression and signaling in murine brain tissue.

The heterotrimeric G-protein α subunit, Gαolf, acts to transduce extracellular signals through G-protein coupled receptors (GPCRs) and stimulates adenylyl cyclase mediated production of the second messenger cyclic adenosine monophosphate. Numerous mutations in the GNAL gene, which encodes Gαolf, have been identified as causative for an adult-onset dystonia. These mutations disrupt GPCR signaling cascades in in vitro assays through several mechanisms, and this disrupted signaling is hypothesized to lead to dystonic motor symptoms in patients. However, the cells and circuits that mutations in GNAL corrupt are not well understood. Published patterns of Gαolf expression outside the context of the striatum are sparse, conflicting, often lack cell type specificity, and may be confounded by expression of the close GNAL homolog of GNAS. Here, we use RNAScope in-situ hybridization to quantitatively characterize Gnal mRNA expression in brain tissue from wildtype C57BL/6J adult mice. We observed widespread expression of Gnal puncta throughout the brain, suggesting Gαolf is expressed in more brain structures and neuron types than previously accounted for. We quantify transcripts at a single cell level, and use neuron type specific markers to further classify and understand patterns of GNAL expression. Our data suggests that brain regions classically associated with motor control, initiation, and regulation show the highest expression of GNAL, with Purkinje Cells of the cerebellum showing the highest expression of any neuron type examined. Subsequent conditional Gnal knockout in Purkinje cells led to markedly decreased intracellular cAMP levels and downstream cAMP-dependent enzyme activation. Our work provides a detailed characterization of Gnal expression throughout the brain and the biochemical consequences of loss of Gαolf signaling in vivo in neurons that highly express Gnal.

Peripherally induced movement disorders in the stomatognathic system after oral surgical or dental procedures.

OBJECTIVES: Peripherally induced movement disorders (PIMD) are hyperkinetic movement disorders that can occur after injury to a part of the body. This study aimed to identify PIMD in the stomatognathic system following dental or oral surgical procedures. MATERIALS AND METHODS: A total of 229 patients with PIMD (144 women and 85 men; mean age: 53.4 years) triggered by oral surgical or dental interventions were evaluated retrospectively. RESULTS: The average latency between the procedures and onset of PIMD was 14.3 days. Oral surgery (40.2%), including tooth extraction, trauma treatment, and other surgical procedures, was the most frequent trigger of PIMD. This was followed by general dental treatment, including periodontal, endodontic, and restorative procedures (36.7%), prosthetic treatment (19.7%), and orthodontic treatment (3.5%). PIMD consisted of oromandibular dystonia (73.8%), functional (psychogenic) movement disorders (11.4%), orolingual dyskinesia (7.9%), and hemimasticatory spasms (5.7%). CONCLUSIONS: These results suggest that even minor alterations in normal anatomy or physiology after dental procedures may result in PIMD in predisposing patients. CLINICAL RELEVANCE: Dental professionals should be aware that although infrequently, PIMD can develop after various dental treatments. If such symptoms precipitate, the attending physician should properly explain them to the patient and provide appropriate treatment or consultation with a movement disorder specialist.

Oromandibular dystonia as a cause of temporomandibular disorder (Case report) / Distonia oromandibular como causa de disfunção temporomandibular (Relato de caso)

Temporomandibular disorders (TMD) can have multiple etiologies, including oromandibular dystonia (OMD). However, in a few cases, the OMD can evolve from cervical dystonia (CD), leading to severe bone degeneration. The purpose of this case report of a 64-year-old woman presenting to the Outpatient Neurology Clinic of the Federal University of Bahia is to illustrate the development of oromandibular dystonia with temporomandibular joint (TMJ) dysfunction after 10 years of cervical dystonia. Clinical examination showed bone degeneration of the mandibular ramus and right TMJ click, a prevalent sound in patients with temporomandibular disorders when they open their mouths or chew. After onabotulinum toxin type A injections in the right lateral pterygoid muscle, the patient improved in swallowing and pain. This case highlights the importance of close follow-up of cervical dystonia patients to identify new dystonic muscles. In our patient, lateral pterygoid muscle involvement was followed by several comorbidities, such as dysphagia and jawbone abnormalities.

Os distúrbios temporomandibulares (DTM) podem ter múltiplas etiologias, incluindo a distonia oromandibular (DO). No entanto, em raros casos, a DO pode evoluir a partir da distonia cervical (DC) e raramente pode levar a degeneração óssea. O objetivo deste relato de caso de uma mulher de 64 anos atendida no Ambulatório de Neurologia da universidade Federal da Bahia é ilustrar o desenvolvimento de distonia oromandibular com disfunção da articulação temporomandibular (ATM) após 10 anos de distonia cervical. O exame clínico mostrou degeneração óssea do ramo mandibular e clique na ATM direita, um som prevalente em pacientes com distúrbios temporomandibulares quando abrem a boca ou mastigam. Após injeções de toxina botulínica tipo A no músculo pterigoideo lateral direito, a paciente apresentou melhora na deglutição e na dor. Este caso destaca a importância do acompanhamento próximo de pacientes com distonia cervical para identificar novos músculos distônicos. Em nossa paciente, o envolvimento do músculo pterigoide lateral foi seguido por várias comorbidades, como disfagia e anormalidades ósseas da mandíbula.

Rehabilitation for Functional Dystonia: Cases and Review of the Literature.

BACKGROUND: Functional dystonia (FD) is a common subtype of functional movement disorder. FD can be readily diagnosed based on positive signs and is potentially treatable with rehabilitation. Despite this, clinical outcomes remain variable and a gold standard approach to treatment is lacking. CASES: Here we present four cases of axial and limb functional dystonia who were treated with integrated rehabilitation and improved. The therapy approach and clinical outcomes are described, including videos. LITERATURE REVIEW: A literature review evaluated the published treatment strategies for the treatment of functional dystonia. Out of 338 articles, 25 were eligible for review and included mainly case reports and case series. Most patients received more than one treatment modality. Non-invasive therapies, commonly physiotherapy and psychological approaches were mostly associated with positive outcomes. Multiple treatments commonly used in dystonia were used, including botulinum toxin injections, pharmacotherapy and surgery, leading to variable outcomes. CONCLUSION: Therapy should be personalized to the clinical presentation. In challenging cases, initiation of a multidisciplinary approach may provide benefit regardless of etiology. Pharmacotherapy should be used judiciously, and surgical therapy should be avoided.

Neuropsychological and social predictors of participation in a deep brain stimulation study of Parkinson's disease and dystonia.

Objectives: Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson's disease (PD) and dystonia. Methods: Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours. Results: Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped ( b ) CI b =45.0 to 249.0, p b =0.016, and estimate=-95.1, CI b =-159.9 to -49.2, p b =0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed (R 2 =0.284, estimate=67.7, CI b =20.1 to 119.9, p b =0.019). Discussion: Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.

Botulinum Toxin and Deep Brain Stimulation in Dystonia.

Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The European Federation of Neurological Societies (EFNS) and the International Parkinson and Movement Disorders Society (MDS) recommend DBS for dystonia after failure of botulinum toxin (BoNT) and other oral medications for dystonia treatment. In addition, several long-term studies have demonstrated the continuous efficacy of DBS on motor and quality of life (QoL) scores. However, there are only a few reports comparing the overall impact of surgical treatment in BoNT protocols (e.g., dosage and number of selected muscles before and after surgery). This retrospective multicenter chart-review study analyzed botulinum toxin total dosage and dosage per muscle in 23 dystonic patients before and after DBS surgery. The study's primary outcome was to analyze whether there was a reduction in BoNT dosage after DBS surgery. The mean BoNT dosages difference between baseline and post-surgery was 293.4 units for 6 months, 292.6 units for 12 months, and 295.2 units at the last visit. The median total dose of BoNT in the preoperative period was 800 units (N = 23). At the last visit, the median was 700 units (p = 0.05). This represents a 12.5% reduction in BoNT median dosage. In conclusion, despite the limitations of this retrospective study, there was a significant reduction in BoNT doses after DBS surgery in patients with generalized dystonia.

Hand Dystonia after Focused Ultrasound Thalamotomy in Essential Tremor.

INTRODUCTION: Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for drug-resistant tremor. The most frequent side effects are ataxia, gait disturbance, paresthesias, dysgeusia, and hemiparesis. Here, we report the first case of thalamic hand dystonia rapidly occurring after MRgFUS thalamotomy of the ventral intermediate nucleus (V.im). CASE PRESENTATION: MRgFUS thalamotomy was performed in a 60-year-old left-handed patient for his disabling medically refractory essential tremor. The intervention resulted in a marked reduction of his action tremor. However, the patient developed an unvoluntary abnormal posture in his left hand a few days after the procedure with difficulty holding a cigarette between his fingers. Brain MRI revealed the expected MRgFUS lesion within the right V.im as well as an extension of the lesion anteriorly to the V.im in the ventro-oralis nucleus. Tractography showed that the lesion disrupted the dentato-rubro-thalamic tract as expected with a lesion suppressing tremor. However, the lesion also was interrupted fibers connecting to the superior frontal and pre-central cortices (primary motor cortex, premotor cortex, and supplementary area). We hypothesized that the interventional MRgFUS thalamotomy was slightly off target, which induced a dysfunction within the cortico-striato-thalamo-cortical network and the cerebello-thalamo-cortical pathway reaching a sufficient threshold of basal ganglia/cerebellum circuitry interference to induce dystonia. CONCLUSION: This rare side effect emphasizes the risk of imbalance within the dystonia network (i.e., basal ganglia-cerebello-thalamo-cortical circuit) secondary to V.im thalamotomy.

Distonía laríngea post COVID-19: reporte de dos casos y posible explicación fisiopatogénica

La distonía laríngea (DL), también conocida como disfonía espasmódica, es un desorden focal tarea-específico del movimiento, que afecta primariamente la producción de la voz. Los movimientos distónicos de las cuerdas vocales producen fenómenos diferentes, especialmente quiebres o interrupciones vocales y tensión en el tipo de distonía laríngea aductora (DLAD), e interrupciones y soplo o segmentos áfonos en el tipo abductor (DLAB). Más del 80% de pacientes sufren de DLAD o DEAD (disfonía espasmódica aductora). Dos pacientes de sexo femenino desarrollaron DL un mes después de haber contraído una infección del tracto respiratorio superior causada por COVID-19. Ambas presentaron distonía laríngea de tipo aductor. En el análisis acústico de la vocal /a/ sostenida se han observado quiebres o interrupciones, cambios frecuenciales y aperiodicidad. El rango de habla fue estudiado en ambas pacientes mediante el fonetograma, dando un resultado alterado. Posiblemente la inflamación de los nervios periféricos de la laringe, causada por COVID-19, produjo una alteración sensitiva con una respuesta mal adaptativa en estas pacientes con una base genética quizás predisponente. O la activación inmunológica, o la invasión del germen a través de la vía retrógrada alteraron las redes neuronales involucradas en la génesis de la DL.

Laryngeal dystonia (LD), also known as spasmodic dysphonia, is a task-specific focal movement disorder, primarily affecting voice production. The dystonic movements of the vocal folds result in a varied phenomenology, typically hard vocal breaks and strain in the adductor-type laryngeal dystonia (ADLD), and breathy breaks or aphonia in the abductor-type laryngeal dystonia (ABLD). More than 80% of patients have suffered from ADLD. Two female patients developed LD a month after presenting an upper respiratory tract infection by COVID-19. They had the adductor-type laryngeal dystonia. Through the acoustic study of the vowel /a/ breaks, frequency changes and aperiodicity were observed. Speech was studied using the phonetogram, and the range of speech is altered in both patients. The inflammation of the peripheral nerves of the larynx by COVID-19 produced a sensory alteration, with a maladaptive response in these patients, who perhaps had predisposing genetic basis, or the immunological activation or the invasion of the germ by retrograde pathway altered the neuronal networks involved in the genesis of LD.

Demographic and clinical characteristics of our patients diagnosed with laryngeal dystonia.

PURPOSE: Laryngeal dystonia (LD) is a focal dystonia affecting laryngeal musculature with no known etiology or cure. The present study evaluated the sociodemographic and clinical features of patients diagnosed with LD. MATERIALS AND METHODS: All patients diagnosed with LD at our University Hospital's Ear, Nose, and Throat Department between January 2017 and July 2023 were retrospectively analyzed. The study included 43 patients. RESULTS: Out of the 43 patients, 19 (44%) were male. At the time of diagnosis, the mean age of the patients was 35.1 years (ranging from 17 to 65 years). The mean elapsed time between the first symptom onset and the first diagnosis was 49.2 months (min. 4 months, max. 240 months). Of the participants, 94% had adductor-type LD. None of the patients had a family history of LD. Of the patients, 9 (20%) experienced a life-altering event or trauma just before the onset of symptoms. All patients who consumed alcohol reported symptom relief with alcohol intake. A total of 67.6% of patients stated that their symptoms were triggered by stress. All of our patients received at least one Botulinum toxin injection, with an average of 2.75 dosages per patient. CONCLUSION: The gender distribution was approximately equitable between males and females. There was a tendency for men to receive a diagnosis earlier than women following the manifestation of symptoms. A significant number of patients associate the emergence of their symptoms with a stressful event or traumatic experience. This study represents the initial investigation into the sociodemographic characteristics of patients within the Turkish population.

Concurrent glossopharyngeal neuralgia and oromandibular dystonia resolved after microvascular decompression of the trigeminal and glossopharyngeal nerve: A rare presentation.

Background: This type of pain syndrome occurs suddenly and briefly, beginning unilaterally from one side of the face. Modestly stimulating speech can provoke it, affecting the ear, tongue, throat, and jaw angle. Interestingly, it is the sensory distribution of the auricular and the pharyngeal branches of the cranial nerves IX and X. People have not had a confirmed case of glossopharyngeal neuralgia (GPN), along with oromandibular dystonia (OMD). Nevertheless, usually in the medical literature, this case report supplies information about a patient who has concurrent GPN and OMD. Case Description: A 36-year-old male patient presented with a history of sudden onset of increasing electric pains, which were centered in the middle of the forehead to the depth of the throat and accompanied by uncontrolled movements, repetitive tongue protrusions, jaw movements, and recurrent pervasive gagging reflexes. Magnetic resonance imaging showed that a vascular loop of the superior cerebellar and anterior inferior cerebellar artery on the left side had crossed over and compressed those nerves. Decompression surgery in the left glossopharyngeal and trigeminal nerves cured all the symptoms. Conclusion: The simultaneous occurrence of GPN and OMD is rare, complex, and challenging from the clinician's viewpoint in the management of similar but different pathologies. A detailed history was taken, and a radiological investigation was called to devise a management plan in the context of understanding the pathology of both disorders.

A Giant, Neglected Leiomyosarcoma on the Left Shoulder.

This paper examines the impact of delayed diagnosis and treatment on the prognosis of patients with leiomyosarcomas (LMS). We present a case study highlighting the consequences of neglected LMS, focusing on vascular involvement and metastatic potential. Our findings underscore the importance of early detection and intervention in improving patient outcomes. Additionally, we discuss the challenges associated with diagnosing rare skin LMS and the implications of limited access to medical screening. Through a comprehensive analysis of the literature, we elucidate the critical role of routine surveillance in detecting these malignancies at an earlier stage, thus facilitating timely intervention and potentially curative treatment. This study underscores the urgency of raising awareness among both healthcare providers and the general population about the significance of early detection and prompt management in mitigating the adverse outcomes associated with neglected LMS.

Striatal parvalbumin interneurons are activated in a mouse model of cerebellar dystonia.

Dystonia is thought to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted an established cerebellar dystonia mouse model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe) and striatal neurons were activated in the model. Next, we examined whether administration of a dopamine D1 receptor agonist and dopamine D2 receptor antagonist or selective ablation of striatal parvalbumin (PV, encoded by Pvalb)-expressing interneurons could modulate the involuntary movements of the mice. The cerebellar dystonia mice had a higher number of cells positive for c-fos (encoded by Fos) in the EPN, SNr and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons, than those in control mice. Furthermore, systemic administration of combined D1 receptor agonist and D2 receptor antagonist and selective ablation of striatal PV interneurons relieved the involuntary movements of the mice. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.

Stress-Induced Oculogyric Crisis in Septo-Optic Dysplasia: Case Report.

Introduction: Oculogyric crisis (OGC) is a dystonic movement disorder of varying durations that manifests as bilateral paroxysmal upward eye deviation accompanied by involuntary blinking, tongue protrusion, and autonomic symptoms. Separately, septo-optic dysplasia (SOD) is a congenital disorder involving hypoplasia of the optic nerve as well as hypothalamic and pituitary abnormalities. In the presented case, we report a case of OGC in the setting of SOD with proposed pathogenesis. Case Presentation: A 27-year-old female presented with a history of SOD (optic nerve hypoplasia and hypopituitarism) with acute, recurrent, painless, bilateral, intermittent, simultaneous tonic conjugate upward eye deviation (i.e., OGC) and dystonic body posturing. She experienced her first episode upon meeting her biological sister for the first time at a loud, crowded public restaurant with continued episodes of OGC increasing in frequency and duration over the subsequent months. She later responded well to treatment with carbidopa/levodopa. Conclusion: Based on our current understanding of OGC, we hypothesize that acute stressful life events in the setting of prior hypothalamic-pituitary axis dysfunction secondary to SOD could lower the threshold for developing OGC. Although most cases of OGC are idiopathic, various etiologies including medications, stress, and hormonal imbalance have been postulated as possible pathogenic mechanisms. We describe a case of SOD with OGC, and based upon our review of the English language ophthalmic literature, we believe that our case is novel.

Prevalence and temporal relationship of clinical co-morbidities in idiopathic dystonia: a UK linkage-based study.

While motor and psychiatric phenotypes in idiopathic dystonia are increasingly well understood, a few studies have examined the rate, type, and temporal pattern of other clinical co-morbidities in dystonia. Here, we determine the rates of clinical diagnoses across 13 broad systems-based diagnostic groups, comparing an overall idiopathic dystonia cohort, and sub-cohorts of cervical dystonia, blepharospasm, and dystonic tremor, to a matched-control cohort. Using the SAIL databank, we undertook a longitudinal population-based cohort study (January 1st 1994-December 31st 2017) using anonymised electronic healthcare records for individuals living in Wales (UK), identifying those diagnosed with dystonia through use of a previously validated algorithm. Clinical co-morbid diagnoses were identified from primary health care records, with a 10% prevalence threshold required for onward analysis. Using this approach, 54,166 dystonia cases were identified together with 216,574 matched controls. Within this cohort, ten of the main ICD-10 diagnostic codes exceeded the 10% prevalence threshold over the 20-year period (infection, neurological, respiratory, gastrointestinal, genitourinary, dermatological, musculoskeletal, circulatory, neoplastic, and endocrinological). In the overall dystonia cohort, musculoskeletal (aOR: 1.89, aHR: 1.74), respiratory (aOR: 1.84; aHR: 1.65), and gastrointestinal (aOR: 1.72; aHR: 1.6) disorders had the strongest associations both pre- and post-dystonia diagnosis. However, variation in the rate of association of individual clinical co-morbidities was observed across the cervical, blepharospasm, and tremor dystonia groups. This study suggests an increased rate of specific co-morbid clinical disorders both pre- and post-dystonia diagnosis which should be considered during clinical assessment of those with dystonia to enable optimum symptomatic management.

Pallidal multifractal complexity is a new potential physiomarker of dystonia.

OBJECTIVE: Low-frequency 4-12 Hz pallidal oscillations are being considered as potential physiomarkers for dystonia. We suggest investigating the multifractal properties of pallidal activity as an additional marker. METHODS: We employed local field potentials (LFP) recordings from 23 patients with dystonia who were undergoing deep brain stimulation (DBS) surgery to explore the connection between disease severity and the multifractal characteristics of pallidal activity. Furthermore, we performed an analysis of LFP recordings from four patients, following the externalization of DBS lead electrodes, to investigate the impact of DBS and neck muscle vibration on multifractal parameters. RESULTS: Greater dystonia severity exhibited a correlation with a narrower multifractal spectrum width but higher multifractal spectral asymmetry. Both GPi DBS and muscle vibration in dystonia patients expanded the multifractal spectrum width while restoring multifractal spectral symmetry. Notably, the threshold peak intensities for an increase in multifractal spectrum width substantially overlapped with the optimal volume of tissue activated. A broader multifractal spectrum during DBS corresponded to more favorable clinical outcomes. CONCLUSIONS: Multifractal properties of pallidal neuronal activity serve as indicators of neural dysfunction in dystonia. SIGNIFICANCE: These findings suggest the potential of utilizing multifractal characteristics as predictive factors for the DBS outcome in dystonia.