Steve Wilkinson

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Unilateral pallidal stimulation for Parkinson's disease: Neurobehavioral functioning before and 3 months after electrode implantation

Unilateral pallidotomy is thought to have a low risk for cognitive morbidity. Nonetheless, recent research suggests that some patients experience declines in memory and language and that pallidal stimulation might be a safer treatment for Parkinsons disease (PD). We investigated the neurobehavioral effects of unilateral pallidal stimulation. Nine consecutive PD patients undergoing unilateral deep brain-stimulating electrode implantation in the globus pallidus interna were evaluated with a neuropsychological test battery approximately 1 month before and 3 months after surgery. Patients reported significantly fewer symptoms of anxiety and greater vigor after surgery. There was a trend toward fewer depressive symptoms. Semantic verbal fluency and visuoconstructional test scores declined significantly after surgery. However, among five patients showing declines in semantic verbal fluency, only one patients score declined by more than 2 SD. No patient showed significant decline or improvement in the overall level of cognitive functioning. This study supports the relative safety, in terms of cognitive function, of unilateral pallidal stimulation in PD.

Deep brain stimulation for essential tremor

We examined the effects and safety of deep brain stimulation (DBS) as a treatment for essential tremor (ET).Ten ET patients with disabling medication-refractory tremor underwent stereotactic implantation of a DBS lead in the left Vim thalamic nucleus and completed a 6-month follow-up. The Clinical Tremor Rating Scale and disability assessments were performed at baseline, 1-, 3-, and 6-month follow-up. There were significant improvements in dressing, drinking, eating, bathing, and handwriting as reported by the subjects. Tremor severity, writing, pouring, and spiral and line drawing were significantly improved as rated by the examiner. Improvements persisted through the 6-month follow-up period. Although global disability significantly lessened in the group as a whole, one subject with hand-finger tremor accentuated by writing had no change in disability status. In this 6-month open-label study, DBS was effective and safe in reducing tremor and functional disability in ET. NEUROLOGY 1996;46: 1150-1153

Bilateral thalamic stimulation for the treatment of essential tremor

OBJECTIVE To determine the safety and efficacy of bilateral thalamic stimulation in the treatment of essential tremor (ET). METHODS Nine ET patients with disabling tremor refractory to pharmacotherapy underwent bilateral staged implants. Tremor was assessed by the Fahn-Tolosa-Marin Tremor Rating Scale at baseline 1 (before first implant), baseline 2 (before second implant), and at 6-month and 1-year follow-up. Blinded evaluations were performed at 3 months. Associated changes in speech were evaluated in six patients. There were seven men and two women with a mean age of 73.8 years. RESULTS There was a significant improvement in the mean total tremor score from a baseline of 66.1+/-11.6 to 28.4+/-12.8 12 months after the second surgery. Similarly, the mean motor tremor subscore was 20.1+/-5.0 before the first surgery and improved significantly to 14.1+/-3.6 before the second surgery. Motor tremor scores 6 months after the second surgery (6.0+/-3.7) and 12 months after the second surgery (7.5+/-3.9) also improved significantly relative to the preoperative scores. The mean activities of daily living (ADL) subscore at baseline was 18.2+/-2.9 and improved significantly before the second surgery to 9.0+/-3.2. These ADL scores further improved 6 months (6.2+/-5.2) and 12 months (7.9+/-5.7) following the second surgery, but these gains were not significant. Blinded evaluations also revealed a similar degree of improvement. Complications were noted in five patients: asymptomatic intracranial hematoma (1), postoperative seizures (1), a hematoma over the implanted pulse generator (IPG) (1), lead repositioning (1), and IPG malfunction (1). Adverse effects related to stimulation were mild and resolved with adjustment of the stimulation parameters. Three of the six patients demonstrated worsening of dysarthria with both stimulators on. CONCLUSIONS Bilateral thalamic stimulation is effective in reducing tremor and functional disability in ET; however, dysarthria is a possible complication.

Neuropsychological and quality of life outcome after thalamic stimulation for essential tremor

Objective: To evaluate short-term effects of unilateral thalamic deep brain stimulation (DBS) on cognition, mood state, and quality of life in patients with essential tremor (ET). Background: Unilateral thalamotomy and thalamic DBS are effective in alleviating refractory tremor contralateral to the side of surgery. Thalamotomy can lead to cognitive morbidity, and DBS might be a preferable surgical intervention given potential avoidance or reversibility of such morbidity. Although unilateral thalamic DBS is cognitively safe and leads to quality of life improvement in PD, its neurobehavioral effects in ET are unknown. Methods: Forty patients with ET were administered a broad neuropsychological test battery, measures of mood state, and generic and disease-specific quality of life measures approximately 1 month before and 3 months after surgery (left hemisphere, 38 patients). Results: Unilateral thalamic DBS was associated with significant improvements in tremor and dominant-hand fine visuomotor coordination. Statistically significant but clinically modest gains were observed on tasks of visuoperceptual and constructional ability, visual attention, delayed word list recognition, and prose recall. Only lexical verbal fluency declined significantly after surgery. Patients rated themselves as less anxious after surgery, and they perceived their quality of life as improved significantly. In particular, patients reported improved quality of life with respect to activities of daily living, stigma, emotional well-being, and communication. Conclusions: Unilateral thalamic DBS for ET is cognitively safe and associated with improvements in anxiety and quality of life in the near term and in the absence of operative complications. Patients were better able to carry out activities of daily living after surgery, and they reported improvement in several psychosocial domains of quality of life.

Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor

Objectives: To evaluate the one year cognitive, mood state, and quality of life (QoL) outcomes of unilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). Methods: 40 patients diagnosed with ET completed comprehensive neuropsychological assessments about one month before and three and 12 months after DBS electrode implantation. Data were subjected to multivariate analyses, and significant results were further analysed using univariate techniques. Results: Analyses revealed statistically significant improvements on a cognitive screening measure and in aspects of fine visuomotor and visuoperceptual functions, verbal memory, mood state, and QoL. No group-wise declines in cognition were observed, but more patients showed declines than improvements on language and visual memory tests. Semantic verbal fluency declined significantly in four (10%) of the patients. In these four patients, diminished lexical verbal fluency was present at baseline. Conclusion: Cognitive, mood, and QoL outcomes after one year of DBS for ET are favourable; there were no overall deleterious effects on cognition, and DBS was accompanied by a significant reduction in anxiety and improvements in quality of life. However, preoperative verbal fluency diminution may predispose to further fluency declines after DBS.

Long term safety and efficacy of unilateral deep brain stimulation of the thalamus for parkinsonian tremor

The objective was to investigate the long term safety and efficacy of unilateral deep brain stimulation (DBS) of the VIM nucleus of the thalamus in Parkinsons disease. Twelve patients with Parkinsons disease underwent unilateral DBS of the thalamus for medication resistant tremor between 1994 and 1997. Patients were evaluated with the motor section of the unified Parkinsons disease rating scale (UPDRS) in the medication on state at baseline, 3 months, 12 months, and yearly thereafter. Three patients were lost to follow up. Nine patients had follow up evaluations greater than 24 months and were included in the analyses. The last postsurgical follow up occurred on average 40.0 (SD 17.2) months after surgery. Tremor scores were significantly improved with stimulation on at the long term follow up compared with baseline. There was no significant change in UPDRS motor scores at long term follow up compared with baseline. There was no significant change in any stimulus parameters from 3 months to the long term follow up. Two patients had asymptomatic intracerebral haemorrhages and one patient had a subcutaneous haematoma over the implantable pulse generator site. Stimulus related adverse reactions were mild and easily controlled with changes in stimulus parameters. Two patients had replacement of the implantable pulse generator due to normal battery depletion, one patient had lead repositioning due to migration, and one patient had the lead extension wire replaced due to erosion. In conclusion,unilateral DBS of the thalamus has long term efficacy for treatment of tremor due to Parkinsons disease.

Reduction in voice tremor under thalamic stimulation

We studied the effect of deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus on voice symptoms in seven patients with essential tremor. All had undergone DBS for management of hand tremor. Five of the patients had received unilateral implants; two were treated bilaterally. Each reported improvement in hand tremor with thalamic stimulation (a 1-to-3-point change on a 5-point severity scale). Voice tremor was evaluated with and without stimulation using patient and clinician severity ratings, and acoustic measures (rate and amplitude). Four of the seven patients showed reductions in voice symptoms in at least two of these measures, although degree of change differed (e.g., from 1 to 3 points on the 5-point severity scale). Voice gains typically were restricted to those patients with the more severe symptoms and did not parallel improvements in the upper extremities. It appears that reduced voice tremor may be an additional benefit of DBS for some individuals.

Neuropsychological and quality of life changes following unilateral thalamic deep brain stimulation in Parkinson's disease: a one-year follow-up.

Summary.Background: The long-term neuropsychological and quality of life (QOL) outcomes of unilateral thalamic deep brain stimulation (DBS) in patients with intractable Parkinsons disease (PD) have not heretofore been described. Method: Six patients diagnosed with PD underwent unilateral DBS implantation into a verified thalamic VIM nucleus target. Participants completed presurgical neuropsychological evaluation and follow-up assessment at approximately one year postsurgery. Findings: Compared to their presurgical scores, PD patients exhibited significant improvement on measures of conceptualization, verbal memory, emotional adjustment, and QOL at one-year follow-up. A few nominal declines were observed across the battery of tests. Interpretation: These data provide preliminary support for the long-term neurocognitive safety and QOL improvements following thalamic stimulation in patients with PD.

Pallidotomy microelectrode targeting: neurophysiology-based target refinement.

OBJECTIVE Microelectrode recording can refine targeting for stereotactic radiofrequency lesioning of the globus pallidus to treat Parkinsons disease. Multiple intraoperative microelectrode recording/stimulating tracks are searched and assessed for neuronal activity, presence of tremor cells, visual responses, and responses to kinesthetic input. These physiological data are then correlated with atlas-based anatomic data to approximate electrode location. On the basis of these physiological properties, one or more tracks are selected for lesioning. This study analyzes the track physiological factors that seem most significant in determining the microelectrode recording track(s) that will be chosen for pallidal lesioning. METHODS Thirty-six patients with Parkinsons disease underwent microelectrode-guided pallidotomy. Between one and five microelectrode recording tracks were made per patient. Usually, one (n = 23) or two (n = 12) of these tracks were lesioned. Electrode positions in the x (mediolateral) and y (anteroposterior) axes were recorded and related to track neurophysiological findings and final lesion location. The stereotactic location and sequence of microelectrode tracks were recorded and plotted to illustrate individual search patterns. These patterns were then compared with those noted in other patients. Neurophysiological data obtained from recording tracks were analyzed. A retrospective analysis of track electrophysiology was performed to determine the track characteristics that seemed most important in the surgeons choice of the track to lesion. Track physiological properties included general cell spike amplitude, tremor synchronous neuronal firing, kinesthetically responsive neuronal firing, and optic track responses (either phosphenes reported by the patient during track microstimulation or neuronal firing in response to light stimulus into the patients eyes). Orthogonally corrected postoperative magnetic resonance images were used to confirm the anatomic lesion locations. RESULTS In patients who had a single mapped track lesioned, specific track electrophysiological characteristics identified the track that would be lesioned most of the time (20 of 24 patients). Tracks that exhibited a combination of tremor synchronous firing, joint kinesthesia, and visual responsivity were lesioned 17 (85%) of 20 times. Analysis of intraoperative electrode movement in the x and y axes indicated a significant subset of moves but did not result in microelectrode positioning closer to the subsequently lesioned track. Accuracy of initial electrode movement in the x and y axes was most highly correlated with a measure of first-track electrophysiological activity. The number of microelectrode recording tracks did not correlate with clinical outcome. Anatomic analysis, using postoperative magnetic resonance imaging, revealed that all lesions were placed in the globus pallidus. Most patients (35 of 36) improved after surgery. CONCLUSION The level of electrophysiological activity in the first track was the best predictive factor in determining whether the next microelectrode move would be closer to the ultimately lesioned track. The analysis of electrode track location and neurophysiological properties yields useful information regarding the effectiveness of microelectrode searching in the x and y axes. Within an institution, the application of this modeling method may increase the efficiency of the microelectrode refinement process.