William J. Marks

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:u2003 Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Pallidal deep brain stimulation in patients with cranial–cervical dystonia (Meige syndrome)

Idiopathic cranial–cervical dystonia (ICCD) is an adult‐onset dystonia syndrome affecting orbicularis oculi, facial, oromandibular, and cervical musculature. ICCD is frequently difficult to treat medically. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a highly effective treatment for idiopathic generalized dystonia, however less is known about the effect of GPi DBS on ICCD. In this article, we present the results from a pilot study assessing the effect of GPi DBS in a series of patients with ICCD. Six patients underwent bilateral stereotactic implantation of DBS leads into the sensorimotor GPi. Patients were evaluated with the Burke–Fahn–Marsden dystonia rating scale (BFMDRS) and Toronto western spamodic torticollis rating scale (TWSTRS) before surgery and 6 months postoperatively. At 6 months, patients showed a 72% mean improvement in the BFMDRS total movement score (P < 0.028, Wilcoxin signed rank test). The mean BFMDRS disability score showed a trend toward improvement (P < 0.06). The total TWSTRS score improved 54% (P < 0.043). Despite improvement in dystonia, mild worsening of motor function was reported in previously nondystonic body regions with stimulation in 4 patients. Although GPi DBS was effective in these patients, the influence of GPi DBS on nondystonic body regions deserves further investigation.

Locations of movement‐related cells in the human subthalamic nucleus in Parkinson's disease

The subthalamic nucleus (STN) is an emerging target for deep brain stimulator (DBS) implantation for the treatment of advanced Parkinsons disease (PD). Understanding the somatotopic organization of the STN is important for surgical navigation within the nucleus. We analyzed intraoperative data obtained during 54 procedures for the implantation of STN stimulators to assess the locations of movement‐related cells. Cells were considered movement‐related if they exhibited modulation of the cell discharge during passive movement of the contralateral upper or lower extremity. Microelectrode track reconstructions were plotted on a human brain atlas, using the location of the DBS electrode from postoperative magnetic resonance images as a registration mark in reconstructing microelectrode track locations. Movement‐related cells were predominantly located in the dorsal part of the nucleus. The majority of the cells were related to proximal joint manipulation. Arm‐related cells were located laterally and at the rostral and caudal poles, whereas leg‐related cells were located medially and centrally. The finding of three or more leg‐related cells on a given microelectrode track was predictive of a medial localization within the motor area. Our findings are consistent with the small number of published studies on STN somatopy in the human and the nonhuman primate.

Quantitative 1H magnetic resonance spectroscopy and MRI of Parkinson's disease

Magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (MRS) of the substantia nigra, basal ganglia, and cerebral cortex were performed on 10 patients with Parkinsons disease (PD) and 13 age‐matched, healthy control subjects. Compared to controls, PD patients had approximately 24% lower creatine in the region of the substantia nigra and smaller volumes of the putamen (11%), globus pallidus (16%), and prefrontal cortex (6%; all P < 0.05). No other significant between‐group differences were found in nine regions examined. Thus, quantitative MRI may show regional neurodegenerative changes outside the substantia nigra in PD but PD‐linked extranigral metabolic abnormalities, if they exist, may be difficult to detect with current 1H MRS methods. In additional, exploratory tests, volumes of the caudate (r = −0.56), putamen (r = −0.66), and globus pallidus (r = −0.60; all P < 0.05) were negatively correlated with the volume of the substantia nigra pars compacta in controls. In PD these correlations did not hold. Instead, pallidal volume in PD was positively correlated with compacta volume (r = 0.64; P < 0.05). This relationship suggests that basal ganglia volumes may be influenced by dopaminergic innervation from the substantia nigra in normal and PD subjects.

Neuropsychological performance following staged bilateral pallidal or subthalamic nucleus deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) has the potential to significantly reduce motor symptoms in advanced Parkinsons disease (PD). Controversy remains about non-motor effects of DBS and the relative advantages of treatment at two brain targets, the globus pallidus internus (GPi) and the subthalamic nucleus (STN). We investigated effects of DBS on neuropsychological functioning in 42 patients with advanced PD randomly assigned to receive staged bilateral DBS surgery of either the GPi or STN. Patients underwent neuropsychological assessment prior to and 6 months after unilateral surgery. Twenty-nine subsequently underwent surgery to the contralateral side and completed a second follow-up neuropsychological evaluation 15 months later. Unilateral treatment resulted in small but statistically significant reductions in performance on several measures, including verbal fluency and working memory. A similar pattern was observed after bilateral treatment. Reductions in verbal associative fluency were significant only after left-sided treatment. There were few significant differences related to treatment at the two surgical targets. Supplementary analyses suggested that decrements in select neuropsychological domains following DBS are unrelated to age or post-surgical reduction in dopaminergic medication dose. Findings are discussed with reference to possible causes of neuropsychological decline and the need for further controlled studies of specific neuropsychological effects of DBS.

Effects of unilateral subthalamic and pallidal deep brain stimulation on fine motor functions in Parkinson's disease

Deep brain stimulation (DBS) is an effective treatment for selected patients with disabling Parkinsons disease (PD). The two main targets are the subthalamic nucleus (STN) and the globus pallidus internus (GPi), although it has not been established whether stimulation at one target is superior to the other. This prospective randomized study assessed the effects of unilateral DBS of the STN versus GPi on fine motor skills in 33 patients with advanced PD. Stimulation of either the STN (18 subjects) or GPi (15 subjects) in the off medication state significantly improved movement time and dexterity, but had little or no effect on reaction time. Overall, the extent of improvement did not differ between the two targets. The degree of improvement in movement time, but not dexterity, was correlated with the extent of preoperative medication responsiveness. Our findings suggest that DBS of the STN or GPi results in a similar improvement in hand movements at short‐term follow‐up. Preoperative medication responsiveness predicts improvement in some but not other motor tasks.

Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease

Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinsons disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation—or to a control group that receives the DBS treatment alone—has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by “piggybacking” onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain.