Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy.

Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

IQ changes after pediatric epilepsy surgery: a systematic review and meta-analysis.

OBJECTIVE: This systematic review aimed to assess the intellectual outcome of children who underwent surgery for epilepsy. METHODS: A systematic review of electronic databases was conducted on December 3, 2021, for PubMed and January 11, 2022, for Web of Science. The review was conducted according to the PRISMA guidelines. The included studies reported on intelligence quotient (IQ) or developmental quotient (DQ) before and after epilepsy surgery in children. Studies were included, if the patients had medically intractable epilepsy and if the study reported mainly on curative surgical procedures. We conducted a random-effects meta-analysis to determine the mean change of IQ/DQ. RESULTS: Fifty-seven studies reporting on a total of 2593 patients met the inclusion criteria. The mean age at surgery was 9.2 years (± 3.44; range 2.4 months-19.81 years). Thirty-eight studies showed IQ/DQ improvement on a group level, 8 yielded stable IQ/DQ, and 19 showed deterioration. Pooled analysis revealed a significant mean gain in FSIQ of + 2.52 FSIQ points (95% CI 1.12-3.91). The pooled mean difference in DQ was + 1.47 (95% CI - 6.5 to 9.5). The pooled mean difference in IQ/DQ was 0.73 (95% CI - 4.8 to 6.2). Mean FSIQ gain was significantly higher in patients who reached seizure freedom (+ 5.58 ± 8.27) than in patients who did not (+ 0.23 ± 5.65). It was also significantly higher in patients who stopped ASM after surgery (+ 6.37 ± 3.80) than in patients who did not (+ 2.01 ± 2.41). Controlled studies showed a better outcome in the surgery group compared to the non-surgery group. There was no correlation between FSIQ change and age at surgery, epilepsy duration to surgery, and preoperative FSIQ. SIGNIFICANCE: The present review indicates that there is a mean gain in FSIQ and DQ in children with medically intractable epilepsy after surgery. The mean gain of 2.52 FSIQ points reflects more likely sustainability of intellectual function rather than improvement after surgery. Seizure-free and ASM-free patients reach higher FSIQ gains. More research is needed to evaluate individual changes after specific surgery types and their effect on long-term follow-up.

Targeted Molecular Strategies for Genetic Neurodevelopmental Disorders: Emerging Lessons from Dravet Syndrome.

Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the SCN1A gene encoding the voltage-gated sodium channel α subunit Nav1.1. Multiple seizure types, cognitive deterioration, behavioral disturbances, ataxia, and sudden unexpected death associated with epilepsy are a hallmark of the disease. Recently approved antiseizure medications such as fenfluramine and cannabidiol have been shown to reduce seizure burden. However, patients with Dravet syndrome are still medically refractory in the majority of cases, and there is a high demand for new therapies aiming to improve behavioral and cognitive outcome. Drug-repurposing approaches for SCN1A-related Dravet syndrome are currently under investigation (i.e., lorcaserin, clemizole, and ataluren). New therapeutic concepts also arise from the field of precision medicine by upregulating functional SCN1A or by activating Nav1.1. These include antisense nucleotides directed against the nonproductive transcript of SCN1A with the poison exon 20N and against an inhibitory noncoding antisense RNA of SCN1A. Gene therapy approaches such as adeno-associated virus-based upregulation of SCN1A using a transcriptional activator (ETX101) or CRISPR/dCas technologies show promising results in preclinical studies. Although these new treatment concepts still need further clinical research, they offer great potential for precise and disease modifying treatment of Dravet syndrome.

Childhood haemorrhagic stroke: a 7-year single-centre experience.

BACKGROUND: In recent years, there has been increasing research interest in improving diagnostic and management protocols in childhood arterial ischaemic stroke (AIS). However, childhood stroke comprises, in approximately equal parts, both arterial ischaemic and haemorrhagic stroke (HS). OBJECTIVE: The aim of this study was to focus on the aetiology, clinical presentation, treatment and short-term outcome of children with spontaneous intracranial bleeding in a university hospital and elucidate differences to childhood AIS. DESIGN: We performed a retrospective analysis of electronic medical records of children (28 days-18 years) diagnosed with HS between 2010 and 2016. RESULTS: We included 25 children (male child, n=11) with a median age of 8 years 1 month. The most common clinical presentations were vomiting (48%), headache (40%) and altered level of consciousness (32%). In more than half of the patients, HS was caused by vascular malformations. Other risk factors were brain tumour, coagulopathy and miscellaneous severe underlying diseases. Aetiology remained unclear in one child. Therapy was neurosurgical in most children (68%). Two patients died, 5 patients needed further (rehabilitation) treatment and 18 children could be discharged home. CONCLUSIONS: HS differs from AIS in aetiology (vascular malformations as number one risk factor), number of risk factors ('mono-risk' disease), clinical presentation (vomiting, headache and altered level of consciousness) and (emergency) therapy.

TNFRSF1A and MEFV mutations in childhood onset multiple sclerosis.

To investigate frequency and phenotype of TNFRSF1A and MEFV mutations in childhood-onset multiple sclerosis (MS). Twenty-nine clinically well characterized patients were investigated for mutations in exons 2, 3, 4, and 6 of the TNFRSF1A gene and in exons 2, 3, 9, 10 of the MEFV gene. Standardized morbidity ratio (SMR) was used to assess whether the number of observed mutations was higher than expected. Eleven out of 29 patients tested positive for mutations. Heterozygosity for the TNFRSF1A R92Q (rs4149584) variant was found in 6/11 mutation-positive patients. The SMR for R92Q in our pediatric MS population was 4.6 (95% CI 1.7-10.0), 7.0 (95% CI 2.6-15.2), and 13.6 (95% CI 5.0-29.7), depending on reference population. Six patients carried at least one heterozygous MEFV mutation with SMRs of 21.4 (95% CI 7.9-46.6) and 14.6 (95% CI 5.4-31.9). Clinical characteristics of childhood MS patients with or without mutations did not differ significantly. Conclusion One third of our childhood MS patients had a heterozygous mutation in the TNFRSF1A and/or MEFV gene. This proportion by far exceeds the number of mutations expected and was higher than in adult MS patients, suggesting that these mutations might contribute to the pathogenesis of childhood MS.

Vertigo and dizziness in adolescents: Risk factors and their population attributable risk.

OBJECTIVES: To assess potential risk factors for vertigo and dizziness in adolescents and to evaluate their variability by different vertigo types. The role of possible risk factors for vertigo and dizziness in adolescents and their population relevance needs to be addressed in order to design preventive strategies. STUDY DESIGN: The study population consisted of 1482 school-children between the age of 12 and 19 years, who were instructed to fill out a questionnaire on different vertigo types and related potential risk factors. The questionnaire specifically asked for any vertigo, spinning vertigo, swaying vertigo, orthostatic dizziness, and unspecified dizziness. Further a wide range of potential risk factors were addressed including gender, stress, muscular pain in the neck and shoulder region, sleep duration, migraine, coffee and alcohol consumption, physical activity and smoking. RESULTS: Gender, stress, muscular pain in the neck and shoulder region, sleep duration and migraine were identified as independent risk factors following mutual adjustment: The relative risk was 1.17 [1.10-1.25] for female sex, 1.07 [1.02-1.13] for stress, 1.24 [1.17-1.32] for muscular pain, and 1.09 [1.03-1.14] for migraine. The population attributable risk explained by these risk factors was 26%, with muscular pain, stress, and migraine accounting for 11%, 4%, and 3% respectively. CONCLUSION: Several established risk factors in adults were also identified in adolescents. Risk factors amenable to prevention accounted for 17% of the total population risk. Therefore, interventions targeting these risk factors may be warranted.

Pediatric idiopathic intracranial hypertension - Is the fixed threshold value of elevated LP opening pressure set too high?

BACKGROUND: Idiopathic intracranial hypertension (IIH) in children is a rare condition of unknown etiology and various clinical presentations. The primary aim of this study was to evaluate if our pediatric IIH study group fulfilled the revised diagnostic criteria for IIH published in 2013, particularly with regard to clinical presentation and threshold value of an elevated lumbar puncture opening pressure. Additionally we investigated the potential utilization of MR-based and fundoscopic methods of estimating intracranial pressure for improved diagnosis. PATIENTS AND METHODS: Clinical data were collected retrospectively from twelve pediatric patients diagnosed with IIH between 2008 and 2012 and revised diagnostic criteria were applied. Comparison with non-invasive methods for measuring intracranial pressure, MRI-based measurement (MR-ICP) and venous ophthalmodynamometry was performed. RESULTS: Only four of the twelve children (33%) fulfilled the revised diagnostic criteria for a definite diagnosis of IIH. Regarding noninvasive methods, MR-ICP (n = 6) showed a significantly higher mean of intracranial pressure compared to a healthy age- and sex-matched control group (p = 0.0043). Venous ophthalmodynamometry (n = 4) showed comparable results to invasive lumbar puncture. CONCLUSION: The revised diagnostic criteria for IIH may be too strict especially in children without papilledema. MR-ICP and venous ophthalmodynamometry are promising complementary procedures for monitoring disease progression and response to treatment.

Epileptic Seizure, Postictal Hemiparesis, and Hyperleukocytosis.

Introduction: Acute ischemic stroke (AIS) is a rare event in infancy. Besides vasculopathy, thrombophilia, or cardiac disorders, cancer and chemotherapy are known predisposing factors for AIS. Leukemia can be associated with different abnormal coagulation parameters, but severe bleeding or thrombosis occurs rarely. Clinical Course: We report the case of a 2-year-old boy who was presented to our emergency ward after a prolonged seizure with right sided postictal hemiparesis. Cranial computed tomography scan revealed a large infarction and edema due to thrombosis of the left carotid artery, the middle cerebral artery, and the anterior cerebral artery. Laboratory workup showed 196 g/L leukocytes with 75% myeloid blast cells. Immediate exchange transfusion, hydration, and chemotherapy with cytarabine were started. During the hospital course intracranial pressure increased and the patient developed a unilateral dilated pupil unresponsive to light. Cranial computed tomography scan revealed a new infarction in the right middle cerebral artery territory. Refractory increased intracranial pressure and brain stem herniation developed, and the child died 3 days after admission to hospital. Conclusion: Seizures with postictal hemiparesis due to cerebral infarction can be a rare manifestation of acute myeloid leukemia. Leukocytosis and cancer-induced coagulopathy are main reasons for thrombosis and/or hemorrhage. High leukocyte counts need immediate interventions with hydration, careful chemotherapy, and perhaps exchange transfusion or leukapharesis. In the presence of thrombosis, anticoagulation must be discussed despite the risk of bleeding due to hyperfibrinolysis and low platelet counts. Mortality may be reduced by awareness of this rare presentation of leukemia and prompt institution of leucoreductive treatment.

Headache in school children: prevalence and risk factors.

BACKGROUND: Recurrent headache is a common problem in school children. Evaluation generally leads to the diagnosis of a primary headache syndrome (migraine or tension-type headache). This review is addressed to the question whether headaches in school children are becoming more common and, if so, what risk factors are associated with the rise in frequency. METHOD: We selectively searched the PubMed database for pertinent publications that contained the terms "primary headache AND children/adolescent AND risk factors/prevalence." Articles published in either English or German up to April 2013 were considered. Articles on secondary types of headache were excluded. RESULTS: Headaches are becoming more common among school children. At present, 66% to 71% of 12- to 15- year-olds have at least one headache every three months, and 33% to 40% have at least one per week. Headache is often accompanied by other physical and/or emotional manifestations. Studies from Scandinavia reveal increasing prevalence in age groups from 8 years of age and upward. Various studies have identified the following risk factors for headache or for its chronification (up to 5.8-fold elevation of risk): a dysfunctional family situation, the regular consumption of alcohol, caffeine ingestion, smoking, a low level of physical activity, physical or emotional abuse, bullying by peers, unfair treatment in school, and insufficient leisure time. CONCLUSION: Headaches are becoming more common among children and adolescents. They are often associated with other physical and emotional complaints.

Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. METHODS: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. RESULTS: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. CONCLUSIONS: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

Muscle atrophy beyond the clinical effect after a single dose of OnabotulinumtoxinA injected in the procerus muscle: a study with magnetic resonance imaging.

BACKGROUND: Botulinum toxin is a powerful and often used agent to treat dynamic rhytides. Focal and reversible neurogenic atrophy is considered to be the relevant mechanism of action. OBJECTIVE: To investigate the loss and regain of muscular volume in relation to clinical wrinkle severity as assessed using standardized scales. METHODS: The facial procerus and corrugator supercilii muscles were injected in two drug-naïve men with 20 U of onabotulinumtoxinA at five injection points (onA). Two men served as controls (one with the same volume of placebo injection using saline solution, one without any intervention). All subjects underwent 3 Tesla magnetic resonance imaging before and after the injection and 1, 4, 6, 10, and 12 months after the injection. Standardized photographs were taken at each test point. RESULTS: Volumetric muscle analysis revealed a 46% to 48% reduction in procerus muscle volume lasting for 12 months after a single dose of onA; glabellar line severity returned to the drug-naïve status after 6 to 10 months. CONCLUSION: The gap between long-term focal muscular atrophy and regained function remains to be elucidated. Future studies will be needed to investigate the complex interaction between focal neurogenic atrophy and potential compensatory functional muscle changes.

How specific are risk factors for headache in adolescents? Results from a cross-sectional study in Germany.

BACKGROUND: The identified preventable risk factors for primary headache in adolescents are smoking; consumption of coffee or alcoholic mixed drinks; physical inactivity; muscle pain in the head, neck, or shoulder region; and chronic stress. OBJECTIVE: To investigate the interrelation of headache with other health complaints and the specificity of the above-mentioned risk factors for headache in adolescents. METHODS: A total of 1,260 students (grades 10 and 11) filled in questionnaires on headache, dietary, and lifestyle factors. The type of headache and health complaints such as dizziness, abdominal pain, musculoskeletal pains, symptoms of possible fatigue syndrome, and psychic complaints were assessed. RESULTS: Isolated headache was found in 18% of the headache sufferers; most frequently isolated tension-type headache (78.2%). Only among adolescents with a combination of headache (mainly migraine) and other health complaints, significant associations for almost all analyzed risk factors were found. The strength of the associations with the considered risk factors was very similar in all three analyzed strata except for considerably lower odds ratios for isolated headache. CONCLUSION: All analyzed risk factors are nonspecific for headache in adolescents because they also increase the risk for other health complaints. Interventions, therefore, should consider a holistic approach focusing not only on headache but also on a broader spectrum of health complaints.

Prevention of headache in adolescents: population-attributable risk fraction for risk factors amenable to intervention.

INTRODUCTION: Several risk factors for headache have been identified, some of which are potentially amenable to interventions. The potential effect of such interventions can be predicted by the population-attributable risk fraction (PARF). We assessed PARFs of the the following risk factors: neck muscle pain, chronic stress, alcohol consumption, smoking, coffee consumption, and physical inactivity. We studied the maximal possible effect achievable by avoidance of these risk factors. METHODS: Two approaches to estimate PARFs are compared, which assess their cumulative and individual impact of risk factors by age: the Levin formula and the average attributable fraction. RESULTS: The overall impact for removal of all six risk factors amounts to 19.7% for the average attributable fraction. Neck tension and consumption of alcohol ranked as the strongest population-attributable risk factor for any headache. The potential impact for migraine was considerably higher (43.8%). With increasing age, the overall impact of risk factors on headache increases by 18.9%. CONCLUSION: Based on the estimations of the most appropriate approach, up to 20% of headaches in general and up to 43% of migraine in adolescents might be preventable by removing risk factors amenable to intervention, with increasing proportions by age.

Identified risk factors and adolescents' beliefs about triggers for headaches: results from a cross-sectional study.

Although there are few studies on adolescents' beliefs about triggers of headache, none of these compared the associations between perceived and observed triggers. This study aimed at comparing the prevalence of self-perceived and observed risk factors for headache among adolescents. Adolescents from the 10th and 11th grades of high schools answered questionnaires on their headaches and on potential risk factors regarding lifestyle, stress and muscle pain. Individuals reporting to have experienced headache in the preceding 6 months were asked to report what they believed to cause their headache (self-perceived triggers). 1,047 (83 %) of 1,260 adolescents reported headaches. Stress, lack of sleep and too much school work were the most frequently reported self-perceived triggers of headache; in contrast the statistical analysis identified alcohol and coffee consumption, smoking, neck pain, stress and physical inactivity as risk factors for headache. Among individuals with headache, 48 % believed that stress might trigger their headaches, while increased stress scores were only observed in 23 %. In contrast, while 7, 4, 0.3 and 0 % of individuals reporting headache considered consumption of too much alcohol, neck pain, physical inactivity and consumption of coffee might trigger their headache, 56, 51, 36 and 14 %, respectively, were exposed to these risk factors. The prevalence of self-perceived triggers of headache does not correspond to the prevalence of identified risk factors for headaches. While the role of stress was overestimated, the high prevalence of the other confirmed risk factors in adolescents with headache suggests potential for prevention by increasing awareness for these risk factors and appropriate interventions.

Anisotropy of transcallosal motor fibres indicates functional impairment in children with periventricular leukomalacia.

AIM: In children with bilateral spastic cerebral palsy (CP), periventricular leukomalacia (PVL) is commonly identified on magnetic resonance imaging. We characterized this white matter condition by examining callosal microstructure, interhemispheric inhibitory competence (IIC), and mirror movements. METHOD: We examined seven children (age range 11y 9mo-17y 9mo, median age 15y 10mo, four females, three males) with bilateral spastic CP/PVL (Gross Motor Function Classification System level I or II, Manual Ability Classification System level I) and 12 age-matched controls (age range 11y 7mo-17y 1mo, median age 15y 6mo, seven females, five males). Fractional anisotropy of the transcallosal motor fibres (TCMF) and the corticospinal tract (CST) of both sides were calculated. The parameters of IIC (transcranial magnetic stimulation) and mirror movements were measured using a standardized clinical examination and a computer-based hand motor test. RESULTS: Fractional anisotropy was lower in children with bilateral spastic CP/PVL regarding the TCMF, but not the left or right CST. Resting motor threshold was elevated in children with bilateral spastic CP/PVL whereas measures of IIC tended to be lower. Mirror movements were markedly elevated in bilateral spastic CP/PVL. INTERPRETATION: This study provides new information on different aspects of motor function in children with bilateral spastic CP/PVL. Decreased fractional anisotropy of TCMF is consistent with impairment of hand motor function in children with bilateral spastic CP/PVL. The previously overlooked microstructure of the TCMF may serve as a potential indicator for hand motor function in patients with bilateral spastic CP/PVL.

Associations of diet and lifestyle with headache in high-school students: results from a cross-sectional study.

BACKGROUND: Diet and lifestyle are seen as factors which influence headache in adults. However, population-based studies on this issue in adolescents are rare. OBJECTIVE: Aim of the present study was to investigate associations between diet and lifestyle factors and different types of headache, ie, migraine and tension-type headache (TTH) in adolescents. METHODS: A total of 1260 adolescents from the 10th and 11th grades of high schools filled in questionnaires on intake of meals, coffee, nonalcoholic and alcoholic drinks, smoking, and physical activity. Type of headache was classified according to the International Classification of Headache Disorders - 2nd edition. Multiple logistic regression models, adjusted for sex and grade, were calculated. RESULTS: High consumption of cocktails (odds ratio = 3.4; 95% confidence interval 1.9-6.0) and coffee (2.4; 1.3-4.7), smoking (2.7; 1.4-5.1), and lack of physical activity (2.2; 1.3-3.7) were significantly associated with migraine plus TTH episodes, consumption of coffee and physical inactivity particularly with migraine (3.4; 1.6-7.0 and 4.2; 2.2-7.9, respectively) and physical inactivity with TTH (1.7; 1.1-2.7). Skipping of meals or insufficient fluid intake were not associated with any type of headache. CONCLUSIONS: Adolescents with any type of headache might benefit from regular physical activity and low consumption of alcoholic drinks, while for migraine patients a low consumption of coffee should additionally be recommended. Intervention studies are warranted to assess whether psycho-educational programs conferring knowledge of these associations will influence headache-triggering behavior and headache in adolescents.

Early globus pallidus internus stimulation in pediatric patients with generalized primary dystonia: long-term efficacy and safety.

Primary generalized dystonia presents mainly at a young age and commonly is severely disabling. The authors report the long-term follow-up (mean, 73 months; range, 50-101 months) of 5 pediatric patients (mean age at surgery 13 years; range, 8-16 years) undergoing globus pallidus internus deep brain stimulation. Mean improvement in the Burke-Fahn-Marsden movement score was 67.4% (range, 47.0%-87.5%), 75.4% (range, 61.5%-91.7%), and 83.5% (range, 72.0%-93.3%) at 3 months, 12 months, and long-term follow-up (>36 months), respectively. Hardware problems (electrode dislocation/breakage of extension cable, and imminent perforation of extension cable) were observed in 2 patients (operative revision without sequelae). Except for mild dysarthria in 2 patients, no other therapy-related morbidity was observed. The authors found globus pallidus internus stimulation to offer a very effective and safe therapy in pediatric patients with primary dystonia. Early neurosurgical intervention seems to be crucial to prevent irreversible impairment of motor function.

Bilateral pallidal stimulation in children and adolescents with primary generalized dystonia--report of six patients and literature-based analysis of predictive outcomes variables.

INTRODUCTION: Primary generalized dystonia is a rare movement disorder. Medical treatment rarely relieves symptoms. The aim of this study was to investigate the efficacy and safety of bilateral pallidal stimulation in 6 children and adolescents with primary generalized dystonia. In addition, we strived to find predictors for treatment outcome by review and analysis of previously published studies. METHODS: Six patients with primary generalized dystonia underwent chronic bilateral stimulation of the globus pallidus internus. A PubMed and MEDLINE search was performed in order to identify children and adolescents who underwent deep brain stimulation for primary generalized dystonia. The primary efficacy endpoint was the relative change of the Burke-Fahn-Marsden-Dystonia-Rating-Scale (movement score) after surgery. RESULTS: Forty-four patients were found to meet the inclusion criteria. The mean age at onset of the disease was 7.8+/-2.8years and the mean age at surgery was 14.2+/-3.5years. The mean Burke-Fahn-Marsden-Dystonia-Rating-Scale (movement score) was 56.9+/-22.7 before surgery and 23.7+/-23.2 at a mean follow up of 13.0+/-4.8months (p<0.001). The improvement in the DYT1-positive group was significantly higher compared to the DYT1-negative group (77%+/-24% and 44%+/-30%, respectively, p<0.001). A positive correlation between the movement score before and after surgery was found in both the DYT1-positive and DYT1-negative cohort (rs=0.624, p<0.001 and rs=0.734, p<0.001, respectively). CONCLUSION: DBS is an effective treatment in children and adolescents with primary generalized dystonia. Predictive factors for a better treatment outcome are DYT1-positive status and minor motor impairment before surgery.