Dopa-responsive dystonia and paroxysmal dystonic attacks associated with ATP1A3 gene variant.

An 18-year-old man had episodes of severe generalised dystonia, from aged 7 months and becoming progressively more frequent. He also had gradually developed interictal limb dystonia. He was initially diagnosed with paroxysmal kinesigenic dyskinesia but he did not improve with several medications. A levodopa trial led to levodopa-induced dyskinetic movements. However, a lower titration of 25 mg of levodopa two times per day substantially improved his motor features and quality of life. Laboratory investigations and MR scans of the brain were unremarkable. Whole-exome sequencing identified a pathogenic variant in the ATP1A3 gene. The ATP1A3-spectrum disorders include non-classical phenotypes such as paroxysmal dystonic attacks. A response to dopamine response is unusual in these disorders. This case highlights the importance of levodopa trials in early-onset dystonia cases.

New-Onset Focal Task Specific Oromandibular Dystonia in Association with Quran Recitation: A Case Series.

Background: Focal task-specific dystonia is a form of isolated focal dystonia that occurs during the performance of a specific skilled motor task. The occurrence of oromandibular dystonia (OMD) specifically in association with the recitation of Quranic verses have been rarely reported in the literature, in non-native Arabic-speaking patients. This case series describe a rare type of focal task-specific dystonia that occurs exclusively by reciting Quran in native Arabic-speaking patients, which has never been reported, to the best of our knowledge. Methods: In this case series, we identified five patients with new-onset OMD that was exclusively induced by reciting Quran. Cases were evaluated in our Movement Disorders outpatient clinic at Ibn Sina hospital; the main tertiary neurology center in Kuwait, between 2015 and 2023. Results: Five cases (3 males, 2 females) were identified in this study. Mean age of onset of the symptoms was 52.3 ± 4.1 years, while the median duration of the symptoms prior to diagnosis was 3 years. All patients were native Arab-speaking, with no previous history of other types of dystonia. No identifiable risk factors could be obtained including exposure to dopamine blocking agents or antipsychotics, or history of oral or dental surgery. Patients underwent a full clinical, laboratory, and radiological evaluation. All patients had OMD dystonia in varying forms and severity, while two patients had additional spasmodic dysphonia/ blepharospasm on progressive recitation. Most patients had minimal improvement with combination of oral medications and speech therapy. Four patients received botulinum toxin injections with better results. Discussion: The mental and physical stress in attempting to recite the Quranic verses could have contributed to the development of OMD. Moreover, the increased demand on the muscles of the jaw, lips, and tongue during recitation can trigger the dystonic symptoms. Highlights: OMD exclusively during Quran recitation is a rare phenomenon, and expands the spectrum of task-specific focal dystonia described in the literature. It was found to be distressing to the patients and a challenge to treat. Prompt recognition could minimize unnecessary testing and procedures, and facilitate earlier treatment.

Advances in targeting neurotransmitter systems in dystonia.

Dystonia is characterised as uncontrolled, often painful involuntary muscle contractions that cause abnormal postures and repetitive or twisting movements. These movements can be continuous or sporadic and affect different parts of the body and range in severity. Dystonia and its related conditions present a huge cause of neurological morbidity worldwide. Although therapies are available, achieving optimal symptom control without major unwanted effects remains a challenge. Most pharmacological treatments for dystonia aim to modulate the effects of one or more neurotransmitters in the central nervous system, but doing so effectively and with precision is far from straightforward. In this chapter we discuss the physiology of key neurotransmitters, including dopamine, noradrenaline, serotonin (5-hydroxytryptamine), acetylcholine, GABA, glutamate, adenosine and cannabinoids, and their role in dystonia. We explore the ways in which existing pharmaceuticals as well as novel agents, currently in clinical trial or preclinical development, target dystonia, and their respective advantages and disadvantages. Finally, we discuss current and emerging genetic therapies which may be used to treat genetic forms of dystonia.

Clinical Observation of Botulinum Toxin Injection in the Treatment of Focal Dystonia and Muscle Spasm.

Dystonia and muscle spasms are a group of common and unfavorable clinical neurological symptoms. The use of botulinum toxin (BTX-A) abroad has achieved good results in the treatment of various movement disorders characterized by involuntary or abnormal muscle contractions. It is expected to open up a new field for the treatment of myelodysplastic syndromes (MDs) such as focal dystonia and muscle spasm. There are theoretical and practical implications for the diagnosis and development of some effective neurological treatments. The efficacy of BTX-A in the treatment of various focal dystonia and muscle spasm disorders is as follows: symptoms were improved to varying degrees after injection of Botox or botulinum toxin type A (CBTX-A), but Botox or CBTx. There was no significant difference in the efficacy of A. 30.4% of patients had complete remission, 57.8% had significant remission, and 8.9% had partial remission. Among them, HFS and BS had the best curative effect, and the symptoms were significantly improved by 95.3% and 89.4%, respectively. The efficacy of CD was also satisfactory, with 75.5% of the patients showing significant improvement in symptoms, followed by Meg/OMD (OMD) with 73.3% and SD with 3.3%. The efficacy of WC is poor, and functional improvement is uncertain. Other forms of focal dystonia and spasticity also showed significant functional improvement in 60% of patients. Most patients start to see effects within 1 week after BTX-A injection, symptoms gradually improve, and the bridge of curative effect is reached in 2-4 weeks, and the healing effect lasts for about 3-5 months on average. The overall severity of adverse effects was not severe and resolved spontaneously within a few days to ten weeks, with the most concerning complications being ptosis and dysphagia.

Botulinum Toxin Therapy in Writer's Cramp and Musician's Dystonia.

Task-specific focal dystonia is characterized by muscle contraction(s) during a specific task, resulting in abnormal postures or movements. Specifically, writer's cramp involves the upper extremity during the act of writing. Musician's dystonia has a highly variable presentation, and thus makes therapeutic options more limited. Treatments include oral pharmacologic agents, neuromodulation, surgery and, most often, botulinum toxin (BoNT) injection. Selection of target muscles for toxin injection continues to be an area of active research for these task-specific movements. We present a review of the literature selected from a predefined search of the MEDLINE and ClinicalTrials.gov databases. We include six controlled studies of botulinum toxin for the management of writer's cramp and focal task-specific dystonia (FTSD), including musician's dystonia. Overall, 139 patients were included across all studies, with 99 individuals injected for writer's cramp and the remaining 40 individuals with FTSD. The age range of all patients was 18-80 years old. We included studies that utilized only the BoNT-A serotype. These studies utilized various severity scales to quantify response to toxin injection, with ratings of instrument or pen control included as subjective ratings. Of the included 139 patients in this review, pooled data for toxin response show that 73% of patients who received the drug demonstrated improvement. Specific techniques for muscle localization and targeting were difficult to study as variable methods were employed. This remains an area of ongoing exploration.

Anesthetic Management of a Child With Rapid-Onset Dystonia-Parkinsonism (DYT12-ATP1A3): A Case Report.

Rapid-onset dystonia-parkinsonism also known as DYT12-ATP1A3 is an extremely rare neurological disease. Patients develop dystonia, bradykinesia, postural instability, dysarthria, and dysphagia. Injection of botulinum toxin is the first-choice treatment for focal dystonia. We report the case of a 14-year-old patient diagnosed with rapid-onset dystonia-parkinsonism who was scheduled for injection of botulinum toxin in his upper limbs under general anesthesia. To our knowledge, there is no previous report about the anesthetic management of patients with rapid-onset dystonia-parkinsonism.

[Anesthesia in patients with dopa-responsive dystonia (Segawa syndrome) : Presentation of the pathophysiology, clinical picture and approach based on two case reports]. / Anästhesieführung bei Patienten mit Dopa-responsiver Dystonie (Segawa-Syndrom) : Darstellung der Pathophysiologie, Klinik und Vorgehensweise anhand zweier Fallberichte.

Segawa syndrome (dopa-responsive dystonia [DRD]) is a rare neurometabolic disorder characterized by progressive dystonia, diurnal variation and tremors. It is caused by an enzymatic defect (a mutation of the GTPCH1 gene located on chromosome 14q) in the synthesis of tetrahydrobiopterin, an important substrate for dopamine synthesis. In the case of early correct diagnosis, clinical symptoms are well-controlled by levodopa therapy. The disease has several features which may lead to organ dysfunctions (e.g. torticollis, scoliosis, dysphagia and immobilization), which may be of concern for the anesthesiologist. Presenting two case reports of female patients undergoing elective cesarean section and breast cancer surgery, the main principles of perioperative management are discussed. Either techniques of regional or general anesthesia can be performed safely. Preoperative medication with levodopa should not be interrupted. Pharmacological agents with an antidopaminergic mode of action have to be avoided as well as significant pain and emotional stress situations in the perioperative period. Surgery in an ambulatory setting may not be recommended.

[Alternating hemiplegia]. / Al'terniruyushchaya gemiplegiya.

Alternating hemiplegia, a rare neurological disease that manifests in children under the age of 18 months, is characterized by transient episodes of hemiparesis of an alternating nature in the waking period. In addition to transient hemiparesis, neurological symptoms in the form of choreoathetosis, ataxia, dystonia, autonomic dysfunction, ocular apraxia, nystagmus, seizures, dysarthria and intellectual disorders may develop. Mutation in the ATP1A3 gene is the cause of the disease in more than 75% of patients. In some cases, the use of flunarizine, adenosine triphosphate and a ketogenic diet can reduce the frequency and duration of hemiplegic attacks. The authors report a case of a patient with alternating hemiplegia caused by a heterozygous mutation in exon 8 of the ATP1A3 gene (chr19: 42489098A>T, rs606231428), resulting in an amino acid substitution at position 335 (p.Val335Asp, NM_001256214.1). The use of flunarizin in a dose of 5 mg/day significantly reduces the number and duration of seizures, while oral adenosine-5-triphosphoric acid in a dose of 20 mg/kg/day is not effective.

Refractory Open Jaw Oromandibular Tardive Dystonia with a Sensory Trick, Treated with Botulinum Toxin: A Case Report.

Jaw-opening oromandibular dystonia (O-OMD) is a clinical subtype of OMD, commonly resistant to treatment. Here, we report a distinct case of tardive O-OMD with a characteristic sensory trick, successfully treated with high-dose botulinum toxin (BTX) injection. A 34-year-old male patient presented with involuntary jaw opening, tongue protrusion, dysarthria, and mild cervical dystonia. The patient reported improved abilities to talk and close his mouth after putting something, like a cigarette, between his teeth. After an unsuccessful treatment with anticholinergic medications, the patient received electromyography-guided BTX injection to the lateral pterygoids (through an extraoral approach), sternocleidomastoids, trapezius, tongue, and platysma muscles. Following the injection, the patient reported marked improvements in his ability to talk and close his mouth without using his sensory trick. One month later, we detected a 58.2% improvement in the Abnormal Involuntary Movement Scale score. Therefore, high-dose BTX injection may be an effective alternative in refractory O-OMD.

Consensus of the Iberoamerican Oculoplastic Society for diagnosis and management of facial dystonia. / Consenso de la Sociedad Iberoamericana de Oculoplástica para el diagnóstico y manejo de las distonías faciales.

OBJECTIVE: To propose guidelines for the diagnosis and treatment of facial dystonia prepared by a group of experts in orbit and oculoplastics from the Iberoamerican Oculoplastic Society. MATERIAL AND METHODS: An interactive discussion between the expert panel and those attending the 6th Iberoamerican Society of Oculoplastics Congress, which took place at the Hospital Nuestra Señora de la Luz in Mexico City on 22 October 2018, providing their personal experience based on evidence for diagnosis and treatment of facial dystonia. Around 200 ophthalmologists specialised in oculoplastics from North, Central and South America, Spain, and Portugal were involved. Discussion was focused on the following themes: pathophysiology, diagnosis, medical management, and surgical management. CONCLUSIONS: Facial dystonia diagnosis is clinical; therefore, image studies are rarely needed. The ophthalmologist is generally the first physician to be consulted, and is able to be the treating physician, with the exception of specific cases of hemifacial spasm where management with neurosurgery may be beneficial. Botulinum toxin is the treatment of choice. Treatment with oral neuroleptics and myectomy of the orbicularis oculi muscle are reserved for refractory cases, since these do not have an adequate clinical response as first choice treatments. Persistent use of botulinum toxin does not modify the natural course of the disease.

The use of opioids in children receiving intrathecal baclofen therapy.

PURPOSE: We hypothesized that children on chronic intrathecal baclofen therapy (ITB) may require less analgesics for postoperative pain control and are at higher risk of developing opioid-induced respiratory depression postoperatively. The aims of this study are to review children on chronic intrathecal baclofen therapy receiving opioids after major surgery and to determine the incidence complications in this population. METHOD: We conducted a retrospective cohort study comparing 13 children on ITB, who underwent posterior spinal fusion surgery, to 17 children with spina bifida that received the same surgery. RESULTS: On postoperative day 0 (POD 0), four children (40%) had respiratory depression in the baclofen group compared to none in the control group. Desaturation was significantly more frequent in children in the ITB group compared to those of the control group on POD 0; oversedation was recorded in 8 (80%) children in the baclofen group vs. 3 (17.6%) in the control group. Desaturation, respiratory depression, and oversedation were significantly more frequent on POD 0 in children in the baclofen group compared with children in the control group. CONCLUSIONS: The findings of the current study suggest that children on chronic intrathecal baclofen therapy require lesser amounts of opioids for postoperative pain control and are at a greater risk of developing postoperative respiratory depression and excessive sedation compared to patients without baclofen therapy.

Medical Management of Movement Disorders.

Pharmacological treatment is the cornerstone in the management of movement disorders. Although most available treatment options have no impact on the underlying process of each movement disorder, symptomatic therapies can significantly improve patient's quality of life and level of disability. Here, we review the current knowledge on clinical symptomatic management of Parkinson's disease (both early and advanced stages), essential tremor, dystonia, and chorea. Ideally, treatment should be carried out by specialists with reasonable experience in movement disorders, as it needs to be tailored for each patient depending on several appraisals, including but not limited to patients' needs, compliance issues, potential side effects, caregiver support, and presence of comorbidities. When medications fail to improve patient's disability, stereotactic surgery is a well-established option for most of these disorders.

Patient Evaluation and Selection for Movement Disorders Surgery: The Changing Spectrum of Indications.

This report summarizes the state-of-the-art and controversies around patient selection for deep brain stimulation (DBS) for various conditions. Parkinson's disease (PD): several class I studies have shown superiority of DBS over best medical treatment for advanced PD with fluctuations and further inclusion criteria. One class I study suggests that PD patients with early motor complications might gain more quality of life if operated within 3 years after the onset of fluctuations. The subthalamic nucleus (STN) is still the standard target. STN DBS has an impact on impulse control disorders though the exact mechanism is unclear. Tremor: essential tremor (ET) patients found to be eligible for DBS surgery should first be treated with primidone, propranolol, and with a combined therapy preoperatively. Second-line drugs (i.e., topiramate and gabapentin) may be useful. No class I studies exist for DBS treatment of ET. The optimal target of DBS in ET might be the posterior subthalamic area. Dystonia: there is class I evidence for primary generalized and segmental dystonia and for some botulinum-resistant focal dystonias. The impact of age, symptom duration, and DYT-mutation status in primary dystonia on the outcome of DBS surgery clearly demands more studies. DBS has a role in SCGE-mutation positive myoclonus dystonia and tardive dystonia. Finally, neurostimulation in secondary dystonia might be considered in selected patients based on an individual patient's approach.

Comparison of botulinum toxin and propranolol for essential and dystonic vocal tremors

OBJECTIVES: Vocal tremors, which cause social difficulties for patients, may be classified as resting or action tremors. Of the vocal action tremors, essential and dystonic tremors are the most common. Botulinum toxin and oral medications have been used to treat vocal tremors, but no comparative clinical trials have been performed. The aim of this study was to compare the effects of botulinum toxin injection and the oral administration of propranolol in the treatment of essential and dystonic vocal tremors. METHODS: This clinical trial recruited 15 patients, divided into essential and dystonic vocal tremor groups. Patients in both groups received successive treatment with botulinum toxin and propranolol. The treatments were administered at different times; the order of treatment was randomly selected. Patients were assessed with flexible nasofibrolaryngoscopy and with perceptual and acoustic voice evaluations. A statistical significance level of 0.05 (5%) was used. RESULTS: Botulinum toxin produced statistically significant improvements in perceptual measures of vocal instability in patients with dystonic vocal tremors compared with baseline values and treatment with propranolol. The acoustic measure of variability in the fundamental frequency was significantly lower in patients with dystonic vocal tremors after treatment with botulinum toxin. CONCLUSION: Essential and dystonic vocal tremors responded differently to treatment. Dystonic vocal tremors responded significantly to treatment with botulinum toxin but not oral propranolol. Essential vocal tremors did not respond significantly to either treatment, perhaps due to the small number of patients, which is a limitation of this research.

Progressive delayed hemidystonia following clinically mild traumatic brain injury.

A 16-year-old boy presented with progressive left hemidystonia over 3 years. The possibilities of symptomatic hemidystonia due to focal lesions such as infarct (vasculitis), tumours, tuberculoma, arteriovenous malformations or heredodegenerative disorders such as Wilson disease were considered. Imaging showed a peculiar scar involving right basifrontal region extending upto anterior, centromedian and dorsomedial nuclei of thalamus due to blowout fracture of roof of orbit. This scar was responsible for progressive left hemidystonia. On probing the history, it was revealed that patient had sustained a mild traumatic brain injury (mTBI) 3 years ago. Burke-Fahn-Marsden dystonia severity rating scale showed improvement from 19 to 6 after treatment with tablet trihexyphenidyl 16 mg and clonazepam 1 mg. A linear scar reaching upto thalamus due to blowout fracture of roof of orbit following clinically mTBI is unique. Delayed, progressive hemidystonia has been reported following severe head injury, however is less common following clinically mTBI.

Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition.

Striatal dysfunction is implicated in many movement disorders. However, the precise nature of defects often remains uncharacterized, which hinders therapy development. Here we examined striatal function in a mouse model of the incurable movement disorder, myoclonus dystonia, caused by SGCE mutations. Using RNAseq we found surprisingly normal gene expression, including normal levels of neuronal subclass markers to strongly suggest that striatal microcircuitry is spared by the disease insult. We then functionally characterized Sgce mutant medium spiny projection neurons (MSNs) and cholinergic interneurons (ChIs). This revealed normal intrinsic electrophysiological properties and normal responses to basic excitatory and inhibitory neurotransmission. Nevertheless, high-frequency stimulation in Sgce mutants failed to induce normal long-term depression (LTD) at corticostriatal glutamatergic synapses. We also found that pharmacological manipulation of MSNs by inhibiting adenosine 2A receptors (A2AR) restores LTD, again pointing to structurally intact striatal circuitry. The fact that Sgce loss specifically inhibits LTD implicates this neurophysiological defect in myoclonus dystonia, and emphasizes that neurophysiological changes can occur in the absence of broad striatal dysfunction. Further, the positive effect of A2AR antagonists indicates that this drug class be tested in DYT11/SGCE dystonia.

Pisa syndrome in Parkinson's disease: An integrated approach from pathophysiology to management.

Pisa syndrome was first described in 1972 in patients treated with neuroleptics. Since 2003, when it was first reported in patients with Parkinson's disease (PD), Pisa syndrome has progressively drawn the attention of clinicians and researchers. Although emerging evidence has partially clarified its prevalence and pathophysiology, the current debate revolves around diagnostic criteria and assessment and the effectiveness of pharmacological, surgical, and rehabilitative approaches. Contrary to initial thought, Pisa syndrome is common among PD patients, with an estimated prevalence of 8.8% according to a large survey. Furthermore, it is associated with the following specific patient features: more severe motor phenotype, ongoing combined pharmacological treatment with levodopa and dopamine agonists, gait disorders, and such comorbidities as osteoporosis and arthrosis. The present literature on treatment outcomes is scant, and the uneven effectiveness of specific treatments has produced conflicting results. This might be because of the limited knowledge of Pisa syndrome pathophysiology and its variable clinical presentation, which further complicates designing randomized clinical trials on this condition. However, because some forms of Pisa syndrome are potentially reversible, there is growing consensus on the importance of its early recognition and the importance of pharmacological adjustment and rehabilitation. © 2016 International Parkinson and Movement Disorder Society.

Long-term follow-up for lumbar intrathecal baclofen catheters placed using the paraspinal subfascial technique.

OBJECT Intrathecal baclofen (ITB) is a valuable therapeutic option for patients with spasticity and dystonia. The techniques that place an ITB pump catheter into the subcutaneous fat of a lumbar incision are well described. Because patients who require ITB often have low body fat content, they may be predisposed to catheter-related complications. The senior author used a novel technique to place the catheter in a paraspinal subfascial fashion, and the short-term results were previously published. That study demonstrated no development of hardware erosions, catheter migrations, or CSF leaks within an average follow-up of 5 months. This study followed up on those initial findings by looking at the long-term outcomes since this technique was introduced. METHODS Using the institutional review board-approved protocol, the electronic medical records were reviewed retrospectively for all patients who underwent paraspinal subfascial catheter placement by the senior author. Patients received follow-up with the surgeon at 2 weeks postoperatively and were followed routinely by their physiatrist thereafter. RESULTS Of the 43 patients identified as having undergone surgery by the senior author using the paraspinal subfascial technique between July 2010 and February 2014, 12 patients (27.9%) required reoperation. There were 5 patients (11.6%) who had complications related to the catheter or lumbar incision. No hardware erosions or CSF leaks were identified. These patients received a median follow-up of 3.0 years, with 30 of 43 patients receiving follow-up over 2.0 years. CONCLUSION This follow-up study suggests that the technique of paraspinal subfascial catheter placement translates to long-term decreases in CSF leakage and complications from erosion, infection, and also catheter malfunctions. It does not seem to affect the overall rate of complications.

Intrathecal morphine therapy in the management of status dystonicus in neurodegeneration brain iron accumulation type 1.

Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pallidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient's motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1.