Deep Brain Stimulation of the Globus Pallidus Internus in a Child with Refractory Dystonia due to L2-Hydroxyglutaric Aciduria.

INTRODUCTION: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder marked by progressive and debilitating psychomotor deficits. Here, we report the first patient with L2HGA-related refractory dystonia that was managed with deep brain stimulation to the bilateral globus pallidus internus (GPi-DBS). CASE PRESENTATION: We present a 17-year-old female with progressive decline in cognitive function, motor skills, and language ability which significantly impaired activities of daily living. Neurological exam revealed generalized dystonia, significant choreic movements in the upper extremities, slurred speech, bilateral dysmetria, and a wide-based gait. Brisk deep tendon reflexes, clonus, and bilateral Babinski signs were present. Urine 2-OH-glutaric acid level was significantly elevated. Brain MRI showed extensive supratentorial subcortical white matter signal abnormalities predominantly involving the U fibers and bilateral basal ganglia. Genetic testing identified a homozygous pathogenic mutation in the L-2-hydroxyglutarate dehydrogenase gene c. 164G>A (p. Gly55Asp). Following minimal response to pharmacotherapy, GPi-DBS was performed. Significant increases in mobility and decrease in dystonia were observed at 3 weeks, 6 months, and 12 months postoperatively. CONCLUSION: This is the first utilization of DBS as treatment for L2HGA-related dystonia. The resulting significant improvements indicate that pallidal neuromodulation may be a viable option for pharmaco-resistant cases, and possibly in other secondary metabolic dystonias.

Deep brain stimulation in pediatric dystonia: calls for therapeutic realism over nihilism.

PURPOSE: Pediatric dystonia (PD) has a significant negative impact on the growth and development of the child. This study was done retrospectively to analyze functional outcomes in pediatric patients with dystonia who underwent deep brain stimulation. METHODS: In this retrospective analytical study, all the patients of age less than 18 years undergoing deep brain stimulation (DBS) for dystonia between 2012 and 2020 in a single center were analyzed and their functional outcomes were measured by the Burke-Fahn-Marsden-dystonia-rating-scale (BFMDRS). RESULTS: A total of 10 pediatric patients were included with a mean age of onset, duration of disease, and age at surgery being 5.75 years, 7.36 years, and 13.11 years, respectively, with a mean follow-up of 23.22 months. The mean pre-DBS motor score was 75.44 ± 23.53 which improved significantly at 6-month and 12-month follow-up to 57.27 (p value 0.004) and 50.38 (p value < 0.001), respectively. Limbs sub-scores improved significantly at both the scheduled intervals. There was a significant improvement in disability at 1-year follow-up with significant improvement in feeding, dressing, and walking components. There was a 27.34% and 36.64% improvement in dystonia with a 17.37% and 28.86% reduction in disability at 6 months and 12 months, respectively. There was a positive correlation between the absolute reduction of the motor score and improvement in disability of the patients at 6 months (rho = 0.865, p value 0.003). CONCLUSIONS: DBS in PD has an enormous role in reducing disease burden and achieving a sustainable therapeutic goal.

Actigraph-based quantification of sleep in children with dystonia undergoing deep brain stimulation.

OBJECTIVE: Dystonia is among the most common pediatric movement disorders and can manifest with a range of debilitating symptoms, including sleep disruptions. The duration and quality of sleep are strongly associated with quality of life in these individuals and could serve as biomarkers of dystonia severity and the efficacy of interventions such as deep brain stimulation (DBS). Thus, this study investigated sleep duration and its relationship to disease severity and DBS response in pediatric dystonia. METHODS: Actigraphs (wearable three-axis accelerometers) were used to record multiday sleep data in 22 children with dystonia, including 6 patients before and after DBS implantation, and age- and sex- matched healthy controls. Data were preprocessed, and metrics of sleep duration and quality were extracted. Repeated-measures statistical analyses were used. RESULTS: Children with dystonia slept less than typically developing children (p = 0.009), and shorter sleep duration showed trending correlation with worse dystonia severity (r = -0.421, p = 0.073). Of 4 patients who underwent DBS and had good-quality data, 1 demonstrated significantly improved sleep (p < 0.001) postoperatively. Reduction in dystonia severity strongly correlated with increased sleep duration after DBS implantation (r = -0.965, p = 0.035). CONCLUSIONS: Sleep disturbances are an underrecognized marker of pediatric dystonia severity, as well as the effectiveness of interventions such as DBS. They can serve as objective biomarkers of disease burden and symptom progression after treatment.

Long-Term Outcomes of Deep Brain Stimulation for Pediatric Dystonia.

BACKGROUND: Deep brain stimulation (DBS) has been utilized for over two decades to treat medication-refractory dystonia in children. Short-term benefit has been demonstrated for inherited, isolated, and idiopathic cases, with less efficacy in heredodegenerative and acquired dystonia. The ongoing publication of long-term outcomes warrants a critical assessment of available information as pediatric patients are expected to live most of their lives with these implants. SUMMARY: We performed a review of the literature for data describing motor and neuropsychiatric outcomes, in addition to complications, 5 or more years after DBS placement in patients undergoing DBS surgery for dystonia at an age younger than 21. We identified 20 articles including individual data on long-term motor outcomes after DBS for a total of 78 patients. In addition, we found five articles reporting long-term outcomes after DBS in 9 patients with status dystonicus. Most patients were implanted within the globus pallidus internus, with only a few cases targeting the subthalamic nucleus and ventrolateral posterior nucleus of the thalamus. The average follow-up was 8.5 years, with a range of up to 22 years. Long-term outcomes showed a sustained motor benefit, with median Burke-Fahn-Marsden dystonia rating score improvement ranging from 2.5% to 93.2% in different dystonia subtypes. Patients with inherited, isolated, and idiopathic dystonias had greater improvement than those with heredodegenerative and acquired dystonias. Sustained improvements in quality of life were also reported, without the development of significant cognitive or psychiatric comorbidities. Late adverse events tended to be hardware-related, with minimal stimulation-induced effects. KEY MESSAGES: While data regarding long-term outcomes is somewhat limited, particularly with regards to neuropsychiatric outcomes and adverse events, improvement in motor outcomes appears to be preserved more than 5 years after DBS placement.

Subthalamic Nucleus Stimulation in Pediatric Isolated Dystonia: A 10-Year Follow-up.

OBJECTIVE: To evaluate the short-term and long-term clinical effectiveness and safety of subthalamic nucleus deep brain stimulation (STN-DBS) for medically intractable pediatric isolated dystonia. METHODS: Using a longitudinal retrospective design, we assessed the clinical outcomes of nine patients who underwent STN-DBS for treatment-refractory pediatric isolated dystonia one decade ago (mean age at surgery: 15.9 ± 4.5 years). The primary clinical outcome used was assessed by retrospective video analyses of patients' dystonia symptoms using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Clinical assessments were performed at baseline, 1-year follow-up (1-yr FU), and 10-year follow-up (10-yr FU). Adverse side effects, including surgery-related, device-related, and stimulation-related effects, were also documented. RESULTS: After STN-DBS surgery, the mean improvement in the BFMDRS motor score was 77.1 ± 26.6% at 1-yr FU and 90.4 ± 10.4% at 10-yr FU. Similarly, the mean BFMDRS disability score was improved by 69.5 ± 13.6% at 1-yr FU and by 86.5 ± 13.9% at 10-yr FU. The clinical improvements gained at 10-yr FU were significantly larger than those observed at 1-yr FU. Negative correlations were found between the duration of disease to age at surgery ratio (DD/AS) and the improvements in the BFMDRS motor score and total score at 1-yr FU and 10-yr FU. CONCLUSION: To our knowledge, this study provides the first clinical evidence for the short- and long-term effectiveness and safety of STN-DBS for pediatric isolated dystonia. Additionally, putative evidence is provided that earlier STN-DBS intervention in patients with refractory pediatric isolated dystonia may improve short- and long-term clinical outcomes.

A Systematic Review of Botulinum Toxin Injection in Pediatric Dystonia.

Botulinum toxin (BT), a first-line treatment for focal dystonias in adults, has gained USA Food and Drug Administration approval for pediatric upper and lower extremity spasticity and sialorrhea, though its use in children younger than 2 years old is still considered off-label treatment for all pathologies. Dosing, treatment strategies and outcome measures lack international consensus, and they are often extrapolated from adult or spasticity guidelines. This review aims to evaluate the best available evidence on the efficacy and safety of BT therapy in pediatric dystonia (age under 21 years old), isolated or associated with other medical conditions. A comprehensive search in PubMed, Scopus and Web of Science was conducted, including only articles in English. Although no randomized controlled trials are still present, 12 articles were included with an overall of 57 patients. All the papers demonstrate that BT can improve motor function, decrease pain and ameliorate quality of life, with minimal adverse effects in pediatric patients affected by pure or mixed dystonic motor disorders. Despite the low level of evidence, our review shows that BT could be an efficacious treatment for these pediatric patients. The frequent generalized involvement, together with the heterogeneous nature of childhood dystonic forms, sometimes intermingled with spasticity, prompts further multicenter clinical trials or prospective studies with a higher level of evidence to shed light on the efficacy and safety profile of BT in pediatric dystonia.

Long term perceptions of illness and self after Deep Brain Stimulation in pediatric dystonia: A narrative research.

BACKGROUND: Deep Brain Stimulation (DBS) is increasingly used in pediatric patients affected by isolated dystonia, with excellent results. Despite well documented long-term effects on motor functioning, information on quality of life and social adaptation is almost lacking. OBJECTIVES: The present study aims to explore the experience of illness and the relation with the device in adult patients suffering from dystonia who underwent DBS surgery in pediatric age. METHODS: A narrative inquiry approach was used to collect patients' narratives of their experience with dystonia and DBS stimulator. A written interview was administered to 8 patients over 18 years old with generalized isolated dystonia who had undergone pallidal DBS implantation in childhood. A thematic analysis was realized to examine the narratives collected. RESULTS: Five main themes emerged: "relationship with the disease", "experience related to DBS procedure", "relationship with one's own body", "fears", "thoughts about future". Despite a general satisfaction in relation to DBS intervention, some patients expressed difficulties, such as the acceptance of changes in one's own body, concerns and fears regarding the device and the future, also considering the critical phase of transition from childhood to adulthood. CONCLUSIONS: These results suggest that further research is needed to understand the contribution of psychological, as much as medical, aspects to the overall outcome of the intervention. The present explorative study encourages a deeper investigations of psychological aspects of patients, in order to plan a tailored care path and to decide whether to suggest a psychological support, both before and after the intervention.

Deep brain stimulation for childhood dystonia: current evidence and emerging practice.

INTRODUCTION: Dystonia, one of the most common childhood movement disorders, is often medically refractory and can lead to profound impacts on the child and their caretakers' quality of life. Limited efficacy of pharmacological treatments has fueled enthusiasm for innovative neurosurgical approaches, notably deep brain stimulation (DBS) as a treatment for refractory dystonia. Areas covered: DBS is increasingly applied to successfully treat childhood dystonia. While generally safe and effective, results vary widely depending on underlying dystonia etiology. The current work synthesizes and highlights advances in research pertaining to the use of DBS for childhood dystonia. The efficacy of DBS for children and youth with dystonia is discussed, with analysis divided among etiological subtypes. The role of DBS as a lifesaving treatment for status dystonicus is also reviewed. Expert commentary: When carefully selected, certain children and youth with dystonia experience significant symptomatic improvement after DBS. Beyond dystonic symptoms, DBS can improve quality of life and reduce caretaker burden.

Update on pediatric dystonias: etiology, epidemiology, and management.

Dystonia is a movement disorder characterized by sustained muscle contractions producing twisting, repetitive, and patterned movements or abnormal postures. Dystonia is among the most commonly observed movement disorders in clinical practice both in adults and children. It is classified on the basis of etiology, age at onset of symptoms, and distribution of affected body regions. ETIOLOGY: The etiology of pediatric dystonia is quite heterogeneous. There are many different genetic syndromes and several causes of symptomatic syndromes. Dystonia can be secondary to virtually any pathological process that affects the motor system, and particularly the basal ganglia. CLASSIFICATION: The etiological classification distinguishes primary dystonia with no identifiable exogenous cause or evidence of neurodegeneration and secondary syndromes. TREATMENT: Treatment for most forms of dystonia is symptomatic and includes drugs (systemic or focal treatments, such as botulinum toxin) and surgical procedures. There are several medications including anticholinergic, dopamine-blocking and depleting agents, baclofen, and benzodiazepines. In patients with dopamine synthesis defects L-dopa treatment may be very useful. Botulinum toxin treatment may be helpful in controlling the most disabling symptoms of segmental or focal dystonia. Long-term electrical stimulation of the globus pallidum internum appears to be especially successful in children suffering from generalized dystonia.