Cognition, adaptive skills and epilepsy disability/severity in patients with Lennox-Gastaut syndrome undergoing deep brain stimulation for epilepsy in the ESTEL trial.

PURPOSE: We previously reported seizure and EEG outcomes of the ESTEL study (Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype). To assess potential cognitive and behavioral changes during chronic, duty-cycle stimulation of bilateral thalamic centromedian nucleus, we compared standardized cognitive and behavioral measurements, as well as caregiver assessments of disability/severity, before implantation and after 3-months stimulation. METHODS: Twenty patients with LGS (17-37 years;13 females) were studied; one participant was not randomized due to DBS device removal, with outcomes of 19 remaining participants reported here. Cognitive and behavioral measurements were performed at baseline (i.e., before DBS implantation), at the end of the blinded stimulation phase, and at study exit. Instruments measured cognition (NIH toolbox cognitive battery, NIHTB-CB), adaptive skills (ABAS-3), epilepsy severity (GASE) and disability (GAD), quality of life (QOLIE-31), and depression (PHQ-9). Changes in scores after 3-months of stimulation relative to baseline were explored using Wilcoxon matched-pairs signed rank tests. RESULTS: After 3-months of stimulation, caregiver-reported epilepsy severity (GASE) and disability (GAD) improved (p<0.05). No other instrument showed a significant change from baseline. Measurements that required direct participant involvement, rather than caregivers, was completed by only a subset of higher-functioning individuals (NIHTB-CB, n = 13; QOLIE-31, n = 3; and PHQ-9, n = 6). In addition to cognitive impairments, behavioral and physical limitations were common obstacles to instrument completion. Standardized scores were hindered by 'floor effects'; however, raw scores better reflected clinical impressions of participants' functioning and were more sensitive to caregiver-reported changes following treatment. CONCLUSION: DBS treatment is associated with reduced epilepsy severity and disability in young adults with LGS. Performing cognitive and behavioral outcome measurement in patients with cognitive impairment is challenging but possible and requires careful selection of instruments and modifications of score interpretation to avoid floor effects.

A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation.

Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

Permanent tremor reduction during thalamic stimulation in multiple sclerosis.

BACKGROUND: Unlike thalamic lesioning, thalamic stimulation is considered a reversible treatment for tremor. However, tremor in multiple sclerosis (MS) can sometimes permanently improve during thalamic stimulation. Such 'permanent tremor reduction' (PTR) has been attributed to limb weakness preventing tremor expression. In this study, 11 consecutive patients with MS tremor treated with thalamic stimulation were assessed for PTR. Eighteen upper limbs had tremor, of which 16 received contralateral stimulation. METHODS: Tremor severity and limb strength were assessed preoperatively, early postoperatively (within 1 year) and late postoperatively (after 3 years). Tremor severity was rated using validated clinical scales both on and off stimulation. Following explantation, the parenchyma surrounding three electrode tracts was examined with MRI. RESULTS: At final review (mean 5.2 years) PTR was evident in 11 of the 18 upper limbs with tremor. PTR often rendered stimulation redundant. PTR could occur when limb strength was conserved and could arise remotely from the initial surgery. PTR was significant (and universal) in limbs that received long-term (>2 years) effective (tremor suppressing) stimulation. PTR was not a significant finding in limbs that had not received long-term, effective stimulation. Contralateral to a limb with PTR, MRI revealed a thalamic lesion adjacent to the electrode tract. Thalamic lesions were not identified contralateral to two limbs without PTR. CONCLUSIONS: MS tremor often permanently improves during thalamic stimulation, even when limb strength is conserved. PTR may simply reflect natural history. Alternatively, these findings appear consistent with the recent proposal that thalamic stimulation in MS might promote local 'demyelinative lesioning.'