Predicting functional gains in a stroke trial.

BACKGROUND AND PURPOSE: A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment. METHODS: Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains. RESULTS: Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment. CONCLUSIONS: Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention.

Long-term evaluation of deep brain stimulation of the thalamus.

OBJECT: The effects of thalamic deep brain stimulation (DBS) on essential tremor (ET) and Parkinson disease (PD) have been well documented, but there is a paucity of long-term data. The aim of this study was to evaluate the long-term safety and efficacy of DBS of the ventralis intermedius nucleus (VIM) of the thalamus for PD and ET. METHODS: Thirty-eight of 45 patients enrolled at five sites completed a 5-year follow-up study. There were 26 patients with ET and 19 with PD undergoing 29 unilateral (18 ET/11 PD) and 16 bilateral (eight ET/eight PD) procedures. Patients with ET were evaluated using the Tremor Rating Scale, and patients with PD were evaluated using the Unified Parkinson's Disease Rating Scale. The mean age of patients with ET was 70.2 years and 66.3 years in patients with PD. Unilaterally implanted patients with ET had a 75% improvement of the targeted hand tremor; those with bilateral implants had a 65% improvement in the left hand and 86% in the right compared with baseline. Parkinsonian patients with unilateral implants had an 85% improvement in the targeted hand tremor and those with bilateral implants had a 100% improvement in the left hand and 90% improvement in the right. Common DBS-related adverse events in patients receiving unilateral implants were paresthesia (45%) and pain (41%), and in patients receiving implants bilaterally dysarthria (75%) and balance difficulties (56%) occurred. Device-related surgical revisions other than IPG replacements occurred in 12 (27%) of the 45 patients. CONCLUSIONS: Thalamic stimulation is safe and effective for the long-term management of essential and Parkinsonian tremors. Bilateral stimulation can cause dysarthria and incoordination and should be used cautiously.

Stimulation of the motor cortex for disabling essential tremor.

OBJECTIVE: To examine the safety and efficacy of targeted stimulation of the motor cortex as a treatment for essential tremor (ET). PATIENTS AND METHODS: At the University of Kansas Medical Center, two patients with essential tremor received stimulation of the (contralateral) motor cortex using an investigational implantable pulse generator (IPG). Patients were evaluated with the Fahn Tolosa Marin tremor rating scale (TRS) at baseline, 1 week and 4 weeks after surgery, both with stimulation turned on and turned off. Both patients also received neuropsychological assessments at baseline and again after surgery. RESULTS: Patient 1 was a 75-year-old male with tremor for 20 years. His baseline total TRS score was 61 and his TRS 1 month after surgery was 57. His IPG was set at 30 Hz, 3 mA and 250 micros pulse width. Patient 2 was a 60-year-old male with tremor for over 10 years. His baseline total TRS was 47 and it was 43, 1 month after surgery. His IPG was set at 50 Hz, 5 mA and 250 micros pulse width. There were no adverse effects. CONCLUSION: Cortical stimulation of the primary hand motor cortex contralateral to the dominant hand was ineffective for the treatment of ET with the stimulation parameters used in this study. Future research examining other stimulation parameters is necessary to determine if there is a role for cortical stimulation in the treatment of ET.

Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up.

OBJECT: Bilateral subthalamic nucleus (STN) stimulation is increasingly used in patients with advanced Parkinson disease (PD). This study was performed to evaluate the long-term efficacy and safety of bilateral STN stimulation in cases of PD. METHODS: The authors performed a prospective, open-label study in patients with PD who underwent bilateral STN stimulation. The authors compared motor scores and activities of daily living (ADL) scores based on the Unified PD Rating Scale (UPDRS) obtained before surgery while patients were in the medication-off state with scores obtained at follow-up evaluations of these patients while in the medication-off/stimulator-on state. Data contained in patient diaries were also compared. Thirty-three patients with PD were evaluated 12 months postoperatively and 19 were evaluated at a mean follow-up time of 28 months. A comparison between UPDRS scores obtained in patients in the medication-off/stimulator-on state and those obtained when patients were in the baseline medication-off state showed a 27% improvement in ADL scores and a 28% improvement in motor scores after surgery. There was a 57% reduction in the use of levodopa-equivalent medication doses. The percentage of the waking day that patients were in the medication-on state increased from 38 to 72%. Surgical complications included seizures (three patients), confusion (five patients), hemiballismus (one patient), and visual disturbance (one patient). Stimulation-related adverse effects were mild. Device-related events included nine lead replacements, seven lead revisions, six extension replacements, and 12 implantable pulse generator (IPG) replacements; one IPG was cleaned and one IPG was placed in a pocket because of the presence of a shunt. CONCLUSIONS: Bilateral STN simulation is associated with a significant improvement in the motor features of PD. Device-related events were common in the first 20 patients who underwent surgery, often requiring repeated surgeries.

High frequency thalamic stimulation for inoperable mesial temporal epilepsy.

PURPOSE: To assess the safety, tolerability and efficacy of high-frequency periodic thalamic stimulation in inoperable mesial temporal epilepsy and the usefulness of intracranially evoked responses for assessment of anatomical uniformity of lead placement. METHODS: Four subjects were implanted with leads aimed at the anterior thalamic nuclei. Six weeks later, Soletra IPGs were activated using parameters similar to the closed-loop trial's (mean: 175 Hz; 4.1 V; 90 mus; 1 min ON, 5 min OFF). Efficacy was assessed by comparing percentage change in seizure frequency over a 6-month baseline versus a 36-month treatment period, using a within-subjects repeated measures design. Tolerability and safety were similarly monitored. Evoked responses elicited by thalamic stimulation were recorded from depth electrodes in the amygdalo-hippocampal regions and compared intra and interindividually. RESULTS: All subjects completed the study, tolerated stimulation and had no serious adverse effects. Mean reduction in seizure frequency was 75.6% (t =-8.24; p < or = 0.01) (range: 92% to 53%). Quality of life improved in all. Verification of electrode placement with a software function indicated that stimulated structures were presumably, Anterior thalami, Latero-polaris, Reticulatus Polaris, Ventro-oralis Internus, and Campus Forelii. Evoked responses from stimulated sites were heterogeneous, intra and interindividually, also suggesting a lack of uniformity in lead placement. CONCLUSIONS: High-frequency, periodic, round-the-clock thalamic stimulation seems safe, well tolerated and efficacious for inoperable mesial temporal epilepsy. Identification of clinically useful parameters may be facilitated by brief closed-loop trials. Selective stimulation of a single structure may not be feasible at certain intensities, nor required for efficacy. Evoked responses may be useful for verification of uniformity of target acquisition.

Preoperative clinical predictors of response to bilateral subthalamic stimulation in patients with Parkinson's disease.

BACKGROUND: Younger age and a response to a supra-threshold levodopa challenge have been reported to predict a favorable response to bilateral subthalamic nucleus (STN) stimulation. OBJECTIVE: To identify and evaluate clinical factors which predict a positive outcome after bilateral STN stimulation in patients with Parkinson's disease, using each patient's typical doses of antiparkinsonian medication rather than a supra-threshold levodopa challenge. METHODS: Forty-five Parkinson's disease patients who underwent bilateral STN implantation were included in the study. There were 33 men and 12 women. Mean age and disease duration were 59.4 and 12.7 years, respectively. All patients underwent Unified Parkinson Disease Rating Scale (UPDRS) evaluations in the medication off and on states at baseline and postsurgically with stimulation on at 3, 6 and 12 months. The percentage improvement in UPDRS motor scores at baseline (medication off vs. on) was compared with the percentage improvement after stimulation optimization (baseline medication off vs. follow-up medication off/stimulation on). RESULTS: The preoperative percentage improvement in UPDRS motor scores with antiparkinsonian medications was predictive of the postoperative percentage improvement in the UPDRS motor scores in the medication off/stimulation on state (r = 0.53, p < 0.001). However, preoperative UPDRS motor scores in the medication on state were more strongly correlated with the postsurgical effect of stimulation (r = 0.64, p < 0.001). The postoperative improvement in UPDRS motor scores with stimulation did not correlate with age, disease duration or time to programming optimization. CONCLUSIONS: The preoperative percentage improvement in UPDRS motor scores with antiparkinsonian medications and UPDRS motor score in the medication on state at baseline are the strongest clinical predictors of responsiveness to bilateral STN stimulation.

Automated seizure abatement in humans using electrical stimulation.

The need for novel, efficacious, antiseizure therapies is widely acknowledged. This study investigates in humans the feasibility, safety, and efficacy of high-frequency electrical stimulation (HFES; 100-500 Hz) triggered by automated seizure detections. Eight patients were enrolled in this study, which consisted of a control and an experimental phase. HFES was delivered directly to the epileptogenic zone (local closed-loop) in four patients and indirectly, through anterior thalami (remote closed-loop), to the other four patients for every other automated seizure detection made by a validated algorithm. Interphase (control vs experimental phase) and intraphase (stimulated vs nonstimulated) comparisons of clinical seizure rate and relative severity (clinical and electrographic) were performed, and differences were assessed using effect size. Patients were deemed "responders" if seizure rate was reduced by at least 50%; the remaining patients were deemed "nonresponders." All patients completed the study; rescue medications were not required. There were 1,491 HFESs (0.2% triggered after-discharges). Mean change in seizure rate in the local closed-loop group was -55.5% (-100 to +36.8%); three of four responders had a mean change of -86% (-100 to -58.8%). In the remote closed-loop, the mean change of seizure rate was -40.8% (-72.9 to +1.4%); two of four responders had a mean change of -74.3% (-75.6 to -72.9%). Mean effect size was zero in the local closed-loop (responders: beneficial and medium to large in magnitude) and negligible in the remote closed-loop group (responders: beneficial and medium to large). HFES effects on epileptogenic tissue were immediate and also outlasted the stimulation period. This study demonstrates the feasibility and short-term safety of automated HFES for seizure blockage, and also raises the possibility that it may be beneficial in pharmaco-resistant epilepsies.

Long-term efficacy of globus pallidus stimulation for the treatment of Parkinson's disease.

OBJECTIVE: To determine the long-term efficacy and safety of globus pallidus internus (GPi) stimulation for Parkinson's disease (PD). BACKGROUND: We previously reported 3-month data for 5 patients who underwent GPi stimulation for PD. We now report long-term data on these 5 patients and 4 additional patients. METHODS: Nine PD patients, 5 men and 4 women, with an average age of 49 years and disease duration of 10 years, underwent GPi stimulation. Six patients had staged bilateral implants and 3 patients had unilateral implants. The mean follow-up was 48.5 months. All patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and completed 2-day diaries before and after surgery. RESULTS: There was a 21% improvement in UPDRS Part II (activities of daily living; ADL) scores and a 37% improvement in UPDRS Part III (motor) scores when the longest follow-up in the 'stimulation-on/medication-off' state was compared to the 'medication-off' state at baseline. The UPDRS Part II (ADL) scores improved by 30% and the UPDRS Part III (motor) scores improved by 39% when the longest follow-up in the 'stimulation-on/mediation-on' state was compared to the 'medication-on' state at baseline. As measured by patient diaries, 'on' time increased from 25 to 59% and 'on with dyskinesia' decreased from 42 to 15%. Surgical- and device-related complications included transient hemiparesis in the operating room, postoperative seizures, and implantable pulse generator and lead problems. There were seven device-related events requiring additional surgical procedures. CONCLUSIONS: GPi stimulation continues to be effective for the long-term treatment of the disabling symptoms of PD; however, the physician and patient should be aware that device-related problems are not uncommon and additional surgery may be necessary.

Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria.

Glutaric aciduria type 1 is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase. This disorder mainly affects children. The majority of patients develop a dystonic-dyskinetic syndrome. The dystonia is painful and can cause significant disability. This report documents an 18-month-old child, the youngest reported, who underwent pallidotomy for disabling dystonia. The surgery improved dystonic symptoms, especially pain in this child with minor complications related to the procedure. Pallidotomy is a reasonable option for children with dystonic symptoms secondary to glutaric aciduria.

Thalamic stimulation for midbrain tremor after partial hemangioma resection.

We describe a patient with disabling medication-resistant midbrain tremor developed after partial hemangioma resection, who responded to deep brain stimulation of the thalamus.

Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures.

OBJECTIVE: To assess the surgical and hardware complications in a series of 81 consecutive patients undergoing subthalamic (STN) deep brain stimulation (DBS) for Parkinson disease (PD). METHODS: The authors prospectively documented surgical and hardware complications occurring at the time of surgery and at subsequent neurologic and surgical evaluations for an average of 17 months, ranging from 1 to 54 months. RESULTS: No patient had a serious surgical complication resulting in death or permanent neurologic deficit. One patient had an intracranial hemorrhage but with no permanent deficit. In follow-up, 2.5% had infections requiring system removal, 3.7% had infections requiring implantable pulse generator (IPG) removal, 12.5% had misplaced leads, and 26.2% had hardware complications including lead migration, lead fracture, extension erosion, extension fracture, and IPG malfunction. CONCLUSION: Serious complications leading to permanent neurologic deficit are rare after STN DBS for advanced PD. However, long-term follow-up demonstrated that hardware complications are relatively common, having occurred in approximately 26% of these patients.