Kenneth A. Follett

Bilateral Deep Brain Stimulation vs Best Medical Therapy for Patients With Advanced Parkinson Disease A Randomized Controlled Trial

CONTEXTnDeep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients.nnnOBJECTIVEnTo compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy.nnnDESIGN, SETTING, AND PATIENTSnRandomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006.nnnINTERVENTIONnBilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists.nnnMAIN OUTCOME MEASURESnThe primary outcome was time spent in the on state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events.nnnRESULTSnPatients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage.nnnCONCLUSIONnIn this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00056563.

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

BACKGROUNDnDeep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinsons disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation).nnnMETHODSnAt seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinsons disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinsons Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events.nnnRESULTSnMean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months.nnnCONCLUSIONSnPatients with Parkinsons disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinsons Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65

Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson's disease: results from a randomised, controlled trial

Background The risk of suicide behaviours post–deep brain stimulation (DBS) surgery in Parkinson’s disease (PD) remains controversial. We assessed if suicide ideation and behaviours are more common in PD patients (1) randomised to DBS surgery versus best medical therapy (BMT); and (2) randomised to subthalamic nucleus (STN) versus globus pallidus interna (GPi) DBS surgery. Methods In Phase 1 of the Veterans Affairs CSP 468 study, 255 PD patients were randomised to DBS surgery (n=121) or 6u2005months of BMT (n=134). For Phase 2, a total of 299 patients were randomised to STN (n=147) or GPi (n=152) DBS surgery. Patients were assessed serially with the Unified Parkinsons Disease Rating Scale Part I depression item, which queries for suicide ideation; additionally, both suicide behaviour adverse event data and proxy symptoms of increased suicide risk from the Parkinsons Disease Questionnaire (PDQ-39) and the Short Form Health Survey (SF-36) were collected. Results In Phase 1, no suicide behaviours were reported, and new-onset suicide ideation was rare (1.9% for DBS vs 0.9% for BMT; Fishers exact p=0.61). Proxy symptoms of relevance to suicide ideation were similar in the two groups. Rates of suicide ideation at 6u2005months were similar for patients randomised to STN versus GPi DBS (1.5% vs 0.7%; Fishers exact p=0.61), but several proxy symptoms were worse in the STN group. Conclusions Results from the randomised, controlled phase of a DBS surgery study in PD patients do not support a direct association between DBS surgery and an increased risk for suicide ideation and behaviours.

Deep brain stimulation of globus pallidus interna, subthalamic nucleus, and pedunculopontine nucleus for Parkinson's disease: Which target?

Deep brain stimulation (DBS) is an accepted therapy for people with Parkinsons disease (PD) motor symptoms that are refractory to pharmacologic therapy. Standard DBS targets are globus pallidus interna (GPi) and subthalamic nucleus (STN). The pedunculopontine nucleus (PPN) is being investigated as a novel target. Which target provides the best outcomes is unknown. The utility of GPi and STN as targets has been confirmed in numerous studies, including randomized comparisons of GPi DBS and STN DBS that demonstrated no difference in motor outcomes. DBS at either site improves appendicular motor symptoms, but beneficial effects on axial manifestations of PD such as postural instability or gait dysfunction (PIGD) are less apparent. PPN has been introduced as a DBS target due to failure of GPi and STN DBS to improve PIGD. Small observational studies indicate improved PIGD with PPN DBS, but small blinded trials show only subjective reduction in falls with no other impact on PIGD or other PD manifestations. No single DBS target is superior to the others. Each target offers relative advantages. Further studies are needed to better define the roles of each target, particularly PPN. Choice of target should be individualized according to providers preferences and patients needs.

Effective stimulation distance for current from macroelectrodes

Effective spread of stimulating current from macroelectrodes was measured using antidromic responses of axons of the pyramidal tract as an indicator of excitation. Both monopolar and concentric bipolar electrode configurations were tested with stimulating distances as large as 7mm. The effective stimulation distance was greater from monopolar electrodes especially at greater current strengths, but differences between the two configurations were frequently small and reversals of this trend occurred. There was no statistically significant difference between the estimates of effective stimulation distance made using large and small axons. The shape of current-distance curves was approximately parabolic using both bipolar and monopolar stimulation. A current strength of 0.5 to 1.0 mA will confine effective current from a monopolar electrode to a sphere of 2-mm radius, but will not stimulate all elements within that area. Even in a brain area as homogeneous as the pyramidal tract, there is still a great deal of variability from mean values in effective stimulation distance. Presumably, the variability would be even greater in more heterogeneous regions.

Differential effects of deep brain stimulation target on motor subtypes in Parkinson's disease.

The Veterans Administration Cooperative Studies Program #468, a multicenter study that randomized Parkinsons disease (PD) patients to either subthalamic nucleus (STN) or globus pallidus internus (GPi) deep brain stimulation (DBS), found that stimulation at either target provided similar overall motoric benefits. We conducted an additional analysis of this data set to evaluate whether PD motor subtypes responded differently to the 2 stimulation targets.

Bilateral Deep Brain Stimulation of the Ventral Intermediate Nucleus of the Thalamus for Posttraumatic Midbrain Tremor

Posttraumatic movement disorders are common sequelae of brain injury, occurring in as many as 66% of people suffering traumatic brain injury. Approximately 5% of patients with severe traumatic brain injury have persistent movement disorders, most commonly tremor (1). Posttraumatic midbrain tremor (also known as Holmes or rubral tremor) is particularly disabling because it typically affects the upper extremities and its combination of rest, action, and postural components results in severe functional impairment (1,2). Midbrain tremor is generally refractory to pharmacologic therapy and does not resolve spontaneously (2), so surgical therapies have been offered to some individuals (1). Ablative therapies such as thalamotomy have not been beneficial uniformly (3), and the incidence of neurological complication is relatively high (1). This has led to application of deep brain stimulation (DBS) for the treatment of posttraumatic tremor. DBS for treatment of midbrain tremor has been described in the literature only in limited fashion and with limited follow-up. DBS of the ventral intermediate nucleus (Vim) can reduce posttraumatic tremor, but the frequent occurrence of speech impairment with bilateral DBS has led some authors to conclude that best results are achieved with unilateral DBS (4). We report here the long-term outcome of a patient who underwent bilateral Vim DBS to treat posttraumatic midbrain tremor, in whom durable improvement of tremor and functional status has been achieved without associated speech dysfunction. We provide video and graphic documentation of tremor in the onand off-stimulation conditions.

Cost of deep brain stimulation for the treatment of Parkinson's disease by surgical stimulation sites

To assess costs and effectiveness of deep brain stimulation (DBS) of the internal globus pallidum (GPi) versus subthalamic nucleus (STN) from the provider and societal perspectives for Parkinsons disease (PD) patients in a multicenter randomized trial.

A telencephalospinal projection in the Tegu lizard (Tupinambis teguixin)

Tegu lizards (Tupinambis teguixin) were studied to determine the presence of a homologue of the mammalian corticospinal tract. The sources of telencephalic efferent projections to the spinal cord were determined by evaluating the localization of retrogradely transported horseradish peroxidase applied in the cervical spinal cord. Labeled cells were present in subtelencephalic sites reported previously by other authors and, in addition, were found in the principal sensory and motor nuclei of the trigeminal nerve and in the nucleus of the posterior commissure. A telencephalospinal projection was identified, originating in the ventral caudal telencephalon. Histochemical staining revealed a high concentration of acetylcholinesterase in cells and neuropil in the same area. This tract is suggested to be homologous to the mammalian amygdalospinal tract. No reptilian homologue of the corticospinal tract was identified.