SUMMARYPurpose: Deep brain stimulation (DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus (CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. Methods: Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation-OFF phase of at least 3 months, a 3-month blind stimulation-ON phase, and a 6-month unblinded stimulation-ON phase. The control period was followed by an unblinded long-term extension phase with stimulation-ON in those patients in whom stimulation was thought to be effective. Key Findings: Eleven patients were recruited at King's College Hospital (London, United Kingdom United Kingdom) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60-95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50-91% improvement in the initial 3 months with DBS OFF. Significance: DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes.

The aim of the present study was to investigate in vivo cortical excitability in the human brain. We studied 45 consecutive patients with refractory epilepsy in whom subdural or intracerebral electrodes were implanted for assessment prior to epilepsy surgery. We compared cortical responses to single pulse stimulation (up to 8 mA, 1 ms duration) in areas where seizure onset occurred, with responses recorded elsewhere. Two main types of responses were seen: (i) 'early responses', spikes and/or slow waves starting within 100 ms after the stimulus which were observed in most regions in all patients; and (ii) 'delayed responses', spikes or sharp waves occurring between 100 ms and 1 s after stimulation which were seen in some regions in 27 patients. The distributions of early and delayed responses were compared with the topography of seizure onset. Whereas early responses were seen in most regions and seem to be a normal response of the cortex to single pulse stimulation, the distributions of delayed responses were significantly associated with the regions where seizure onset occurred. We conclude that the presence of delayed responses can identify regions of hyperexcitable cortex in the human brain. The study of delayed responses may improve our understanding of the physiology and dynamics of neuronal circuits in epileptic tissue and may have an immediate clinical application in assessment of candidates for surgical treatment of epilepsy.

The investigated CBSDA has a high sensitivity and an acceptable specificity for triggering VNS. Despite the moderate effects on seizure frequency, combined open- and closed-loop VNS may provide valuable improvements in seizure severity and QOL in refractory epilepsy patients.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Aim The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation (DBS) surgery on outcome in a cohort of children with medically refractory, disabling primary, secondary‐static, or secondary‐progressive dystonias, including neurodegeneration with brain iron accumulation (NBIA). Method Dystonia severity was assessed using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011. Results Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part‐DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow‐up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1–14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary‐static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo–20y); five as having secondary‐progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo–13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1–14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories (Kruskal–Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery (DD/AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and −0.599 respectively). A similar significant negative correlation was found in the secondary‐static dystonia group between outcome at 1 year and DD/AS ratio (−0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months (Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery. Conclusion Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia.