Deep Brain Stimulation for Generalized Dystonia from Secondary Carnitine Deficiency: A Case Report and Literature Review.

BACKGROUND: Carnitine deficiencies result from a metabolic disorder of fatty acid β-oxidation and may lead to organic acidemia, which are thought to be associated with dystonia, epilepsy, autism and developmental delay. Pharmacotherapy has been the dominant therapy, while many refractory patients still require other treatment. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been found to be effective for medically refractory primary dystonia and now it has been proposed to be used for secondary dystonia from mitochondrial metabolic disorder. OBJECTIVE: To investigate the efficacy and safety of DBS treatment in secondary dystonia from organic acid metabolic disorder. METHODS: We present a patient born with secondary carnitine deficiency who had the onset of generalized seizures at age 4.5 months and developed torsion dystonia at age 14. Multiple medical therapies failed to adequately control her symptoms, therefore she received GPi DBS at age 26 years. In addition, we performed a literature review of this therapy in the treatment of organic acid metabolic disorder. RESULTS: Our patient’s dystonia resolved without side effects post-DBS surgery, but intermittent spastic symptoms along with severe pain in her lower extremity persist. Concerning the 8 cases from our literature review, 7 received GPi DBS, and had improvement in motor symptoms. Overall, DBS efficacy was lower than in treatment of primary dystonia. One patient with methylmalonic acidemia received STN DBS and had marked improvement in dystonia and reduction in pain afterwards. CONCLUSION: DBS has become an effective therapy in refractory secondary dystonia from organic acid metabolic disorder. More prospective studies are needed to determine the eligibility and efficacy of this surgical therapy in these cases.

A-72 Neuropsychological Functioning in Primary Dystonia: A Multi-Domain Meta-Analysis

Objective Primary dystonia is conventionally seen as a motor disorder, though growing literature indicates cognitive dysfunction among persons with primary dystonia (PWD). Here, we completed a meta-analysis comparing cognition on clinical measures between PWD and normal controls. Method We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO using a uniform search-strategy to locate original research comparing cognition between PWD and control samples. All analyses were modeled under random-effects. We used Hedge’s g as a bias-corrected estimate of effect size. Between-study heterogeneity was assessed using Cochran’s Q and I2. Results The initial search strategy yielded 866 results. Twenty studies were analyzed (PWD n = 739, control n = 865; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = −0.55, p < 0.001), with low heterogeneity (Q = 23.60, p = 0.21, I2 = 19.49). Trim-and-fill procedure estimated 6 studies missing due to publication bias (adjusted g = −0.47, Q = 44.58). Within-domain effects of primary dystonia were: Motor/Non-Motor Speed = −0.76, Global Cognition/Orientation = −0.65, Language = −0.62, Executive Functioning = −0.50, Learning/Memory = −0.46, Visuospatial/Construction = −0.44, and Simple/Complex Attention = −0.36. Heterogeneity was generally low within domains. Effects were comparable between Speed tasks with (g = −0.85) and without (g = −0.80) a motor component. Meta-regressions indicated age, education, gender, and disease duration were not related to effect sizes. Conclusions PWD consistently demonstrated lower performances on neuropsychological tests compared to controls. Effect sizes were generally moderate in strength, with smallest effects in Simple/Complex Attention, and largest in Motor/Non-Motor Speed. Within the Speed domain, results suggested cognitive slowing beyond effects from motor symptoms. This quantitative summary indicates that PWD experience difficulties in multiple aspects of cognition, as detected by neuropsychological tests.

Dystonia in children

Dystonia is a motor disorder characterized by sustained muscle contractions producing twisting, repetitive, and patterned movements or abnormal postures. Dystonia is among the most commonly observed motor disorders in clinical practice in children. Unlike dystonia in adults that typically remains focal or spreads only to nearby muscle groups, childhood dystonia often generalizes. Classification of dystonia has direct implications for narrowing down the differential diagnosis, choosing the diagnostic work-up, predicting the prognosis, and choosing treatment options. The etiology of pediatric dystonia is quite heterogeneous. The etiological classification distinguishes primary dystonia with no identifiable exogenous cause or evidence of neurodegeneration and secondary syndromes. Dystonia can be secondary to any pathological process that affects the basal ganglia. The treatment options of childhood dystonia include several oral pharmaceutical agents, botulinum toxin injections, and deep brain stimulation therapy. Botulinum toxin treatment is the first choice treatment for most types of focal dystonia. In children it is less used because dystonic forms are mainly generalized, but it might also be helpful in controlling the most disabling symptoms of segmental or generalized dystonia. Long-term electrical stimulation of the globus pallidum internum is now established as an effective treatment for various types of movement disorders including dystonia. However, this method has not yet found its application in Russia due to the difficulty of implementation and the lack of patient routing. To increase the effectiveness of complex therapy of dystonia in children, new pathogenetic methods of treatment of common forms of primary dystonia and dystonic syndromes in the structure of degenerative diseases of the central nervous system are needed, as well as the development of optimal algorithms for the diagnosis and treatment of these patients.

Functional Dystonia: Differentiation From Primary Dystonia and Multidisciplinary Treatments

Dystonia is a common movement disorder, involving sustained muscle contractions, often resulting in twisting and repetitive movements and abnormal postures. Dystonia may be primary, as the sole feature (isolated) or in combination with other movement disorders (combined dystonia), or as one feature of another neurological process (secondary dystonia). The current hypothesis is that dystonia is a disorder of distributed brain networks, including the basal ganglia, cerebellum, thalamus and the cortex resulting in abnormal neural motor programs. In comparison, functional dystonia (FD) may resemble other forms of dystonia (OD) but has a different pathophysiology, as a subtype of functional movement disorders (FMD). FD is the second most common FMD and amongst the most diagnostically challenging FMD subtypes. Therefore, distinguishing between FD and OD is important, as the management of these disorders is distinct. There are also different pathophysiological underpinnings in FD, with for example evidence of involvement of the right temporoparietal junction in functional movement disorders that is believed to serve as a general comparator of internal predictions/motor intentions with actual motor events resulting in disturbances in self-agency. In this article, we present a comprehensive review across the spectrum of FD, including oromandibular and vocal forms and discuss the history, clinical clues, evidence for adjunctive “laboratory-based” testing, pathophysiological research and prognosis data. We also provide the approach used at the Massachusetts General Hospital Dystonia Center toward the diagnosis, management and treatment of FD. A multidisciplinary approach, including neurology, psychiatry, physical, occupational therapy and speech therapy, and cognitive behavioral psychotherapy approaches are frequently required; pharmacological approaches, including possible targeted use of botulinum toxin injections and inpatient programs are considerations in some patients. Early diagnosis and treatment may help prevent unnecessary investigations and procedures, while facilitating the appropriate management of these highly complex patients, which may help to mitigate frequently poor clinical outcomes.

Morphological Abnormalities in the Basal Ganglia of Dystonia Patients

<b><i>Objective:</i></b> The pathophysiology of dystonia is poorly understood. As opposed to secondary forms of dystonia, primary dystonia has long been believed to lack any neuroanatomical substrate. During trajectory planning for DBS, however, conspicuous T2-hyperinstensive signal alterations (SA) were registered within the target region, even in young patients, where ischemia is rare. <b><i>Methods:</i></b> Fifty MRIs of primary dystonia patients scheduled for DBS were analyzed. Total basal ganglia (BG) volumes, as well as proportionate SA volumes, were measured and compared to 50 age-matched control patients. <b><i>Results:</i></b> There was a 10-fold preponderance of percentaged SA within the globus pallidus (GP) in dystonia patients. The greatest disparity was in young patients &#x3c;25 years. Also, total BG volume differences were observed with larger GP and markedly smaller putamen and caudate in the dystonia group. <b><i>Conclusions:</i></b> BG morphology in primary dystonia differed from a control population. Volume reductions of the putamen and caudate may reflect functional degeneration, while volume increases of the GP may indicate overactivity. T2-hyperintensive SA in the GP of young primary dystonia patients, where microvascular lesions are highly unlikely, are striking. Their pathogenic role remains unclear.

Deep Brain Stimulation (DBS) in the treatment of primary dystonia of the pediatric population: a review

Background: Deep Brain Stimulation (DBS) is a neurosurgical technique widely used for the treatment of several pathologies, such as Parkinson’s Disease and dystonias. Dystonias, primary or secondary, have several determining factors, among which we can mention genetic mutations, that, generally, do not respond satisfactorily to drug treatments. The difficult control of dystonias makes its management complex, since they are progressive, and, as a consequence, surgical options are often necessary. Objectives: To identify the impact of the use of DBS on the prognosis of children with primary dystonia. Methods: The present work consists of an integrative literature review, in which a careful search was carried out from databases available on the internet, such as Google Scholar, MedScape, Scielo and PubMed, using the following keywords combined in pairs: deep brain stimulation, pediatrics and primary dystonia. The research was carried out in English and Portuguese and, at the end, 10 articles published between the years 2017 and 2021 were selected. Results: Through analysis, it was observed that DBS proved to be an excellent therapy, with good results, especially for patients with primary dystonia, who were more susceptible to showing improvements in motor symptoms. Of these patients, those who have a mutation in the DYT1 gene seemed to respond better when it comes to disabling symptoms, as well as those who have known genetic etiologies. Conclusions: Although there is a limited number of studies related to the pediatric population, the use of DBS for dystonias, especially primary ones, seems to be an excellent therapeutic option for patients refractory to drug therapy. In any case, studies aimed at this group are still necessary in order to enrich and support the current evidence.