Deep brain stimulation activation volumes and their association with neurophysiological mapping and therapeutic outcomes.

OBJECTIVE: Despite the clinical success of deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD), little is known about the electrical spread of the stimulation. The primary goal of this study was to integrate neuroimaging, neurophysiology and neurostimulation data sets from 10 patients with PD, unilaterally implanted with subthalamic nucleus (STN) DBS electrodes, to identify the theoretical volume of tissue activated (VTA) by clinically defined therapeutic stimulation parameters. METHODS: Each patient specific model was created with a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic and substantia nigra neurons into the context of the imaging data; (3) fitting a three dimensional brain atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the VTA using a diffusion tensor based finite element neurostimulation model. RESULTS: The patient specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. Interestingly, of the five patients exhibiting a greater than 40% improvement in their Unified PD Rating Scale (UPDRS), all but one had the majority of their VTA outside the atlas defined borders of the STN. Furthermore, of the five patients with less than 40% UPDRS improvement, all but one had the majority of their VTA inside the STN. CONCLUSIONS: Our results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.

The persistent effects of unilateral pallidal and subthalamic deep brain stimulation on force control in advanced Parkinson's patients.

The persistent effects of unilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi) or subthalamic nucleus (STN) on specific movement parameters produced by Parkinson's disease (PD) patients are poorly understood. The aim of this study was to determine the effects of unilateral GPi and STN DBS on the force-producing capabilities of PD patients during maximal efforts and functional bimanual dexterity. Clinical and biomechanical data were collected from 14 unilaterally implanted patients (GPi=7; STN=7), at least 13 months post-DBS surgery, during On and Off stimulation in the absence of medication. Unilateral DBS of either location produced a 33% improvement in UPDRS motor scores. Significant gains in maximum force production were present in both limbs during unimanual efforts. The greatest increase in maximum force, for both limbs, was under bimanual conditions. Force in the contralateral limb increased more than 30% during bimanual efforts while ipsilateral force increased by 25%. Unilateral DBS improved grasping force control and consistency of digit placement during the performance of a bimanual dexterity task. The clinical and biomechanical data indicate that unilateral DBS of GPi or STN results in persistent improvements in the control and coordination of grasping forces during maximal efforts and functional dexterous actions. Unilateral DBS implantation of either site should be considered an option for those patients in which bilateral procedures are contraindicated.

Bilateral subthalamotomy in Parkinson's disease: initial and long-term response.

We conducted an open label pilot study of the effect of bilateral subthalamotomy in 18 patients with advanced Parkinson's disease. In seven patients, the first subthalamotomy pre-dated the second by 12-24 months ('staged surgery'). Subsequently, a second group of 11 patients received bilateral subthalamotomy on the same day ('simultaneous surgery'). Patients were assessed according to the CAPIT (Core Assessment Program for Intracerebral Transplantation) protocol, a battery of timed motor tests and neuropsychological tests. Evaluations were performed in the 'off' and 'on' drug states before surgery and at 1 and 6 months and every year thereafter for a minimum of 3 years after bilateral subthalamotomy. Compared with baseline, bilateral subthalamotomy induced a significant (P < 0.001) reduction in the 'off' (49.5%) and 'on' (35.5%) Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at the last assessment. A blind rating of videotape motor exams in the 'off' and 'on' medication states preoperatively and at 2 years postoperatively also revealed a significant improvement. All of the cardinal features of Parkinson's disease as well as activities of daily living (ADL) scores significantly improved (P < 0.01). Levodopa-induced dyskinesias were reduced by 50% (P < 0.01), and the mean daily levodopa dose was reduced by 47% at the time of the last evaluation compared with baseline (P < 0.0001). Dyskinesias occurred intraoperatively or in the immediate postoperative hours in 13 patients, but were generally mild and short lasting. Three patients developed severe generalized chorea that gradually resolved within the next 3-6 months. Three patients experienced severe and persistent postoperative dysarthria. In two, this coincided with the patients exhibiting large bilateral lesions also suffering from severe dyskinesias. No patient exhibited permanent cognitive impairment. The motor benefit has persisted for a follow-up of 3-6 years. This study indicates that bilateral subthalamotomy may induce a significant and long-lasting improvement of advanced Parkinson's disease, but the clinical outcome was variable. This variability may depend in large part on the precise location and volume of the lesions. Further refinement of the surgical procedure is mandatory.

Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough?

Neurophysiological changes in the basal ganglia thalamo-cortical circuit associated with the development of parkinsonian motor signs remain poorly understood. Theoretical models have ranged from those emphasizing changes in mean discharge rate to increased oscillatory activity within the beta range. The present study characterized neuronal activity within and across the internal and external segments of the globus pallidus as a function of motor severity using a staged, progressively severe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsonism in three rhesus monkeys. An increase in coherence between neuronal pairs across the external and internal globus pallidus was present in multiple frequency bands in the parkinsonian state; both the peak frequency of oscillatory coherence and the variability were reduced in the parkinsonian state. The incidence of 8-20Hz oscillatory activity in the internal globus pallidus increased with the progression of the disease when pooling the data across the three animals; however it did not correlate with motor severity when assessed individually and increased progressively in only one of three animals. No systematic relationship between mean discharge rates or the incidence or structure of bursting activity and motor severity was observed. These data suggest that exaggerated coupling across pallidal segments contribute to the development of the parkinsonian state by inducing an exaggerated level of synchrony and loss of focusing within the basal ganglia. These data further point to the lack of a defined relationship between rate changes, the mere presence of oscillatory activity in the beta range and bursting activity in the basal ganglia to the motor signs of Parkinson's disease.

Effect of the distal-balloon protection system on microembolization during carotid stenting.

BACKGROUND: The distal-balloon protection system is being evaluated for its efficacy in preventing embolic neurological events during carotid stenting (CAS). We sought to determine the effect of this system on the frequency of Doppler-detected microembolic signals (MES) during CAS. METHODS AND RESULTS: Using transcranial Doppler, we compared the frequency of MES during CAS in 2 groups: 39 patients without distal protection and 37 who used the distal-balloon protection system (GuardWire). There were no significant differences in the clinical or angiographic characteristics between the 2 groups. Three phases with increased MES counts were identified during unprotected CAS; these were stent deployment, predilation, and postdilation (75+/-57, 32+/-36, and 27+/-25 METS, respectively). The distal-balloon protection significantly reduced the frequency of MES during CAS (MES counts: 164+/-108 in the control versus 68+/-83 in the protection group; P=0.002), particularly during these 3 phases. MES in the protection group were detected predominantly during sheath placement, guidewire manipulation, and distal-balloon deflation. CONCLUSION: Three phases with increased MES counts were identified during unprotected CAS (eg, stent deployment, predilation, and postdilation). The distal-balloon protection system significantly reduced the frequency of MES during CAS, particularly during these 3 phases.

Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis.

BACKGROUND: Carotid stenting is a less invasive percutaneous procedure than carotid endarterectomy for the treatment of carotid stenosis. Reports suggest that it can be performed with periprocedural complication rates similar to those of carotid endarterectomy. The purpose of this study was to determine short- and long-term outcomes in the largest prospective cohort of carotid stenting patients. METHODS AND RESULTS: This study followed 528 consecutive patients (604 hemispheres/arteries) undergoing carotid stenting. There was a 0.6% (n=3) fatal stroke rate and 1% (n=5) nonstroke death rate at 30 days. The major stroke rate was 1% (n=6), and the minor stroke rate was 4.8% (n=29). The overall 30-day stroke and death rate was 7.4% (n=43). Over the 5-year study period, the 30-day minor stroke rate improved from 7.1% (n=7) for the first year to 3.1% (n=5) for the fifth year (P:<0.05 for trend). The best predictor of 30-day stroke and death was age >/=80 years. After the 30-day period, the incidence of fatal and nonfatal stroke was 3.2% (n=31). On Kaplan-Meier analysis, the 3-year freedom from ipsilateral or fatal stroke was 92+/-1%. CONCLUSIONS: Experience from a single group of operators demonstrates that carotid stenting can be performed with an acceptable 30-day complication rate. Late follow-up also demonstrates a low rate of fatal and nonfatal stroke. These results suggest that carotid stenting may be comparable to carotid endarterectomy, and it underscores the clinical equipoise and premise for the National Institute of Health-supported, randomized Carotid Revascularization Endarterectomy Versus Stent Trial comparing carotid stenting with carotid endarterectomy.

Preradiation intracarotid cisplatin treatment of newly diagnosed anaplastic gliomas. The CNS Cancer Consortium.

PURPOSE: This phase II study was performed to assess the response of patients with newly diagnosed, untreated malignant gliomas (anaplastic astrocytoma [AA] and glioblastoma multiforme [GBM]) to intracarotid (IC) cisplatin. PATIENTS AND METHODS: Eligibility criteria included surgical intervention limited to biopsy only, measurable contrast-enhancing tumor, and unilateral tumor location within the vascular territory of one internal carotid artery. Patients were scheduled to receive four infusions of IC cisplatin (75 mg/m2 every 4 weeks) before beginning standard radiotherapy. Twenty-six patients were treated, and 22 were assessable for response. RESULTS: Ten patients (45%) showed a greater than 25% decrease in the enhancing tumor area before radiotherapy with stabilization or improvement of neurologic deficits, and three patients (14%) had a greater than 70% decrease in tumor area. The likelihood of response to IC cisplatin was not clearly linked to patient age, tumor histology, or pretreatment tumor size. Myelosuppression, nephrotoxicity, and ototoxicity were mild. Optic neuropathy occurred in one patient, seizures in two, and fatal postinfusion cerebral edema in one. CONCLUSION: This study design, which permits assessment of the drug sensitivity of the untreated glioma, has shown definite antitumor activity of IC cisplatin in newly diagnosed malignant glioma patients.

Procedural safety and short-term outcome of ambulatory carotid stenting.

BACKGROUND AND PURPOSE: Ambulatory procedures increase patient comfort and enhance cost-effectiveness. We sought to determine the feasibility and safety of ambulatory carotid stenting. METHODS: A selected group of patients was admitted and discharged the same day after the carotid stenting procedure. Immediate and short-term outcomes are reported. RESULTS: A total of 98 ambulatory carotid stenting procedures (98 hemispheres in 92 patients) were performed. There were 66 men (72%), and the mean age was 70+/-9 years. Of the patients, 28% had neurological symptoms related to the treated artery within 3 months before the procedure. Sixteen percent of the patients had prior carotid endarterectomy, 4% had prior ipsilateral neck radiation, and 8% had complete occlusion of the contralateral internal carotid artery. Successful access site hemostasis was ensured in all patients with suture-mediated vascular closure devices in 96 (98%) and manual compression in 2. Clinical follow-up was available for 96% of the patients at a mean time of 6+/-4 months. There were no neurological events, deaths, repeated procedures, or major access site complications. CONCLUSIONS: Ambulatory carotid stenting is both safe and feasible. This approach will enhance the applicability of the procedure by increasing patient comfort and potentially reducing procedural costs.

Complications of gamma knife surgery for Parkinson disease.

BACKGROUND: Many medical centers throughout the world offer radiosurgery with the gamma knife (GK) for pallidotomy and thalamotomy as a safe and effective alternative to radiofrequency ablative surgery and deep brain stimulation for Parkinson disease (PD). The reported incidence of significant complications varies considerably, and the long-term complication rate remains unknown. DESIGN: We describe 8 patients seen during an 8-month period referred for complications of GK surgery for PD. RESULTS: Of the 8 patients, 1 died as a result of complications, including dysphagia and aspiration pneumonia. Other complications included hemiplegia, homonymous visual field deficit, hand weakness, dysarthria, hypophonia, aphasia, arm and face numbness, and pseudobulbar laughter. In all patients, lesions were significantly off target. CONCLUSIONS: The 8 patients with PD seen in referral at our center for complications of GK surgery highlight a spectrum of potential problems associated with this procedure. These include lesion accuracy and size and the delayed development of neurological complications secondary to radiation necrosis. Gamma knife surgery may have a higher complication rate than has been previously appreciated due to delayed onset and underreporting. We believe that the risk-benefit ratio of the GK will require further scrutiny when considering pallidotomy or thalamotomy in patients with PD. Physicians using this technique should carefully follow up patients postoperatively for delayed complications, and fully inform patients of these potential risks.

Tactile spatial acuity and roughness discrimination: impairments due to aging and Parkinson's disease.

We used gratings of alternating ridges and grooves in a quantitative psychophysical investigation of tactile perception in patients with Parkinson's disease (PD) and age-matched normal controls. The groove width required for threshold discrimination of grating orientation was 25% higher in the control subjects compared to younger individuals studied previously (p = 0.004), indicating a small but significant decline in tactile spatial acuity with age. Relative to age-matched controls, patients with PD showed a twofold increase in the tactile spatial threshold (p = 3.07 x 10(-8), with somewhat greater impairment on the side more affected clinically (p = 0.03). Testing with the forearm prone, as compared to supine, produced a small improvement in the acuity of patients (p = 0.01) but not controls (p = 0.26). PD patients were also impaired in tactually discriminating grating roughness: their difference limens were over three times higher than those of controls (p = 5.74 x 10(-5)) for gratings differing in groove width, and over twice as high (p = 0.0003) for gratings differing in ridge width. We conclude that PD significantly impairs performance on these tactile tasks.

Lateralization of brainstem lesions by brainstem auditory evoked potentials.

In eight patients with unilateral pontine and midbrain lesions, brainstem auditory evoked potentials (BAEPs) were studied with ipsilateral (Cz-Ai) and contralateral (Cz-Ac) recordings after monaural stimulation. In all cases, the most prominent abnormality was noted in BAEP generated by stimulating the ear ipsilateral to the lesions. The Cz-Ai and Cz-Ac patterns showed similar abnormalities in five of the patients and dissociated abnormalities in two patients. We conclude that: (1) Lateralization of BAEP is possible in unilateral pontine and midbrain lesions. (2) Monaural stimulation with Cz-Ai and Cz-Ac recordings is essential for lateralization. (3) The BAEP in monaural stimulation is predominantly generated from the auditory structures ipsilateral to the stimulated ear.

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Pathophysiologic basis of surgery for Parkinson's disease.

Dopamine depletion induces a series of changes in the basal ganglia motor circuit that underlie the origin of the cardinal features of Parkinson's disease. It has now been established that hyperactivity of the subthalamic nucleus (STN) is an essential feature of the parkinsonian state. This leads to increased excitatory driving onto the globus pallidum internum (GPi) and substantia nigra reticulata (SNr) which, in turn, overinhibits the motor projections to the thalamus and brainstem. The STN and GPi have become the preferred targets for surgery to treat PD. In keeping with the classic pathophysiologic model, physiologic and neuroimaging studies in patients have shown that lesioning or functional blockades (by deep brain stimulation, or DBS) of these nuclei increased cortical activation, in parallel with clinical improvements of bradykinesia. Neuronal recording during surgery has also shown tremor-related activity in both the STN and GPi. However, the pathophysiologic model of the basal ganglia needs further refinement to provide a more detailed explanation of the origin of both tremor and rigidity in Parkinson's disease and to explain the antidyskinetic effect of surgery of the GPi and STN.

Visual fields in patients with posterior GPi pallidotomy.

The objective of this study was to describe the incidence and types of visual field defects after posterior globus pallidus internus (GPi) pallidotomy for Parkinson's disease. The creation of the pallidotomy lesion carries a risk of damaging neighboring structures such as the optic tract. The reported frequency of visual field defects in patients after pallidotomy varies from 0 to 40%. Goldmann visual field testing was performed on 40 patients who underwent microelectrode-guided posterior GPi pallidotomy. The optic tract was identified during the procedure by listening during microelectrode recording for the evoked responses to light flashes and by assessing stimulation-induced subjective responses. After the first 18 patients, lesioning thresholds were increased from 0.5 to > or =1.0 mA so that the lesion was placed more distant from the optic tract. The location of individual lesions was determined on postsurgical MRI. Three patients (7.5%) had visual field defects likely related to the pallidotomy. These were contralateral homonymous superior quadrantanopias, associated in two patients with small paracentral scotomas. The incidence of visual field defects with the early technique was 11% (2/18) and decreased to 4.5% (1/22) after thresholds for lesioning were increased. Except for the location of the lesion relative to the optic tract (more ventral, adjacent to or extending into the optic tract), no other variable correlated with a post-pallidotomy visual field defect. Microelectrode-guided GPi pallidotomy is a relatively safe procedure as regards visual function even when the optic tract is used as a guide for lesion placement.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Carotid stent-supported angioplasty: a neurovascular intervention to prevent stroke.

Obstructive carotid artery disease is responsible for 60% of strokes in the United States and is the third major cause of death. Stent-supported carotid artery angioplasty has the potential to prevent stroke in thousands of patients and offers a number of potential advantages over surgical revascularization (carotid endarterectomy). Results of the prospective observational study at the University of Alabama at Birmingham indicate that carotid stent-supported angioplasty is safe and probably effective in reducing stroke in patients with high-risk cerebrovascular disease. Technical success was achieved in 99% of 146 procedures; 210 stents were placed in 152 vessels, with only 1 instance of stent thrombosis. The rate of major in-hospital complications was unexpectedly low-only 1 death and 2 major strokes. Seven patients suffered minor strokes, but only 2 were left with minor weakness. When compared with a projected complication rate of 6% had these patients undergone carotid endarterectomy, stenting resulted in fewer major events. At 6-month follow-up, 69 of 74 patients were evaluated by angiography or ultrasound, which detected 8 cases of stent deformation and a restenosis rate of < 5%. Because of these instances of stent deformation, use of the Palmaz (biliary) stent was discontinued. Although 1 patient had a transient ischemic attack, no strokes occurred during follow-up. To date, carotid stenting is an investigational procedure. Cardiovascular interventionalists, industry, and the FDA are encouraged to validate this approach through clinical testing. However, improvements in technique, devices, and adjunctive therapies are needed before the method can be tested in randomized trials.

Elective carotid artery stenting in the presence of contralateral occlusion.

Significant carotid stenosis in the presence of an occluded contralateral artery has a poor prognosis with medical therapy alone. Carotid cross clamping during surgical endarterectomy results in critical flow reductions in patients with inadequate collateral flow, and represents a significant risk for procedural strokes. Carotid stenting is being evaluated as an alternative to endarterectomy. We describe the immediate and late outcome of a series of 26 patients treated with carotid stenting in the presence of contralateral carotid occlusion. The mean age of the patients in this group was 65 +/- 9 years, 23 (89%) were men and 10 (39%) were symptomatic from the vessel treated. The procedural success of carotid stenting in this group of patients was 96%. The mean diameter stenosis was reduced from 76 +/- 15% to 2.8 +/- 5%. There was 1 (3.8%) minor stroke in a patient who developed air embolism during baseline angiography. At late follow-up there was no neurologic event in any patient at a mean of 16 +/- 9.5 months after the procedure. Thus, carotid stenting of lesions with contralateral occlusion can be performed successfully with a low incidence of procedural neurologic complications and late stroke.

Early results of percutaneous intervention for severe coexisting carotid and coronary artery disease.

Fifty-one patients with severe coexisting carotid and symptomatic coronary artery occlusive disease successfully underwent staged or simultaneous coronary angioplasty and carotid stenting. One pericardial effusion and 2 minor strokes with full recovery occurred in the hospital, but no major neurologic events, myocardial infarction, or death were observed and no repeat revascularization was required within the 30-day follow-up.

Carotid artery stenting in patients with high neurologic risks.

Forty-four patient with high neurologic risks (Mayo class IV) successfully underwent carotid artery stenting with combined major stroke and death rates of 4.5%. Late follow-up at a mean of 23 +/- 1.8 months showed 1 non-neurologic death, but no neurologic events or repeat stenting procedures.

Computed tomography in the evaluation of the optic chiasm.

Computed tomography (CT) is the procedure of choice for initial evaluation of patients suspected of having chiasmal or perichiasmal lesions. Over 1000 patients were examined with high resolution CT, using axial and coronal scans, contrast enhancement, multiplanar reformations, and, when indicated, metrizamide CT cisternography. The normal anatomic appearance of the chiasm and neighboring structures are: (1) symmetric or asymmetric enlargement of the chiasm; (2) areas of abnormal density, without or with contrast enhancement, in the chiasm or perichiasmal region; (3) alteration of the suprasellar cistern; and (4) distortion of the anterior-inferior third ventricle.