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Kenneth A. Follett

Deep brain stimulation (DBS) can relieve dyskinesias effectively and safely. This modality is applied most commonly in the treatment of dyskinesias associated with levodopa therapy for Parkinson disease. The subthalamic nucleus (STN) and globus pallidus internus (GPi) are the most common surgical targets. Deep brain stimulation of the GP has a direct antidyskinetic effect, whereas relief of dyskinesias by DBS of the STN depends on postoperative reduction of dopaminergic medications. Outcomes are similar for DBS in these two sites despite the different mechanisms by which the stimulation relieves dyskinesias. Deep brain stimulation of the STN has become the surgical treatment of choice in many movement disorders programs but this modality has not been compared with DBS of the GPi in randomized controlled trials, and the superiority of one site over the other remains unproven. In the absence of data demonstrating superiority, selection of the stimulation target should be individualized to meet the needs of each patient. Selection of the target should be based on the patient's most disabling symptoms, response to medications (including side effects), and the goals of therapy, with consideration given to the different antidyskinetic effects of DBS of the STN and GPi.

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Paul D. Sawin, Vincent C. Traynelis and Kenneth A. Follett

✓ Two cases of spinal epidural hematoma following intravenous administration of recombinant tissue-type plasminogen activator are presented. Both patients received thrombolytic therapy for acute myocardial infarction; back pain and progressive neurological dysfunction ensued, secondary to spinal cord compression caused by epidural hematoma. Both individuals underwent emergency surgery for decompression and hematoma evacuation, resulting in improvement in neurological function. The current status of thrombolytic therapy is reviewed, with emphasis on complications of therapy that require neurosurgical intervention.

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Paul D. Sawin, Kenneth A. Follett, B. Chen Wen and Edward R. Laws Jr.

✓ The first documented case of a symptomatic intrasellar hemangioblastoma is described, occurring in an 11-year-old girl with stigmata of von Hippel—Lindau disease who presented with headaches, progressive bitemporal hemianopsia, and adenohypophysial dysfunction. A subtotal resection of the lesion was achieved with two separate surgical procedures: a transsphenoidal approach and a subfrontal craniotomy. Subsequent growth of residual tumor was treated with combined conventional radiotherapy and stereotactic radiosurgery. Two years following completion of these adjuvant therapies, no residual tumor was evident on magnetic resonance imaging. Previous experience with hemangioblastoma in this region, as well as the rationale for radiotherapy in the treatment of incompletely resected lesions, is reviewed.

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Paul D. Sawin, Vincent C. Traynelis, Gretchen Rich, Bruce A. Smith, Timothy J. Maves, Kenneth A. Follett and Steven A. Moore

✓ The mechanism of action underlying chymopapain (Chymodiactin) chemonucleolysis remains obscure. Radiographic studies suggest that chymopapain does not alter disc fragment size acutely; nonetheless, patients often report symptom resolution within a few days, even hours, of treatment. The authors postulate that, in addition to its chemonucleolytic action, chymopapain may possess antiinflammatory properties. To test this hypothesis, the authors assessed the ability of chymopapain to modulate the activity of the proinflammatory enzyme phospholipase A2 (PLA2) and to ameliorate behavioral changes associated with inflammatory neuropathy in an in vivo model of sciatica.

Thirty-nine male Fischer rats were randomly assigned to one of three treatment groups: 1) saline, 2) betamethasone, or 3) chymopapain. All of the rats underwent unilateral sciatic nerve ligation with loose chromic gut suture to induce inflammatory mononeuropathy. The animals were tested for thermal and mechanical hyperalgesia on Days 0 (preoperation), 7 (pretreatment), and 14 (prior to death). Three animals were killed on Day 0 to determine the baseline PLA2 activity within unmanipulated rat sciatic nerves. On Day 7, three animals from each group were killed to assess PLA2 activity prior to treatment. The remainder were given a single infusion of saline, betamethasone (0.3 mg/kg), or chymopapain (100 pKat U) around the inflamed nerve. On Day 14, the remaining animals were killed and their sciatic nerves were removed. The tissue was homogenized and the PLA2 activity was determined using [14C]arachidonate—labeled Escherichia coli phospholipid membrane as a substrate. Lipids were extracted and separated by thin-layer chromatography.

All animals developed behavioral changes consistent with inflammatory mononeuropathy 24 to 72 hours postoperatively; these included gait disturbance, flexion deformity, and hyperalgesia of the involved hindlimb. The degree of mechanical and thermal hyperalgesia was comparable between groups at Day 7. By Day 14, the thermal hyperalgesia had resolved; the mechanical hyperalgesia was less evident in the betamethasone- and chymopapain-treated groups than in the saline-treated controls (p = 0.003; saline- vs. chymopapain-treated groups p = 0.004; saline- vs. betamethasone-treated groups p = 0.008). The mean PLA2 activity at baseline (Day 0) was 11.6 ± 4.9 nmol phospholipid hydrolyzed per minute per milligram of protein. The PLA2 activity at Day 7 was 74.4 ± 18.2 (ligated side) and 21.2 ± 11.7 (nonligated side). At Day 14, PLA2 activity was reduced in the chymopapain- (47.8 ± 12.3) and betamethasone- (39.7 ± 9.5) treated groups compared with the saline control group (62.3 ± 11.2), (saline- vs. chymopapain-treated groups p < 0.05; saline- vs. betamethasone-treated groups p < 0.01). The PLA2 activity in nonligated specimens was 18.6 ± 10.1.

These data indicate that chymopapain exhibits antiinflammatory properties in vivo, reducing PLA2 activity and ameliorating mechanical hyperalgesia in this model of inflammatory sciatic neuropathy.

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Günther Deuschl, Kenneth A. Follett, Ping Luo, Joern Rau, Frances M. Weaver, Steffen Paschen, Frank Steigerwald, Lisa Tonder, Valerie Stoker and Domenic J. Reda

OBJECTIVE

Several randomized studies have compared the effect of deep brain stimulation (DBS) of the subthalamic nucleus with the best medical treatment in large groups of patients. Important outcome measures differ between studies. Two such major studies, the life-quality study of the German Competence Network for Parkinson’s disease (LQ study) and the US Veterans Affairs/National Institute of Neurological Disorders and Stroke trial (VA/NINDS trial), were compared here in order to understand their differences in outcomes.

METHODS

Unless otherwise noted, analyses were based on those subjects in each study who received a DBS implant (LQ study 76 patients, VA/NINDS trial 140 patients) and who had data for the measurement under consideration (i.e., no imputations for missing data), referred to hereafter as the “as-treated completers” (LQ 69 patients, VA/NINDS 125 patients). Data were prepared and analyzed by biostatisticians at the US Department of Veterans Affairs Cooperative Studies Program Coordinating Center, the Coordinating Center for Clinical Trials Marburg, and Medtronic, under the direction of two authors (G.D. and K.A.F.). Data were extracted from the respective databases into SAS data sets and analyzed using SAS software. Analyses were based on the 6-month follow-up data from both studies because this was the endpoint for the LQ study.

RESULTS

Pre-DBS baseline demographics differed significantly between the studies, including greater levodopa responsiveness (LDR) in the LQ study population than in the VA/NINDS group. After DBS, LQ subjects demonstrated greater improvement in motor function (Unified Parkinson’s Disease Rating Scale, Motor Examination [UPDRS-III]), activities of daily living (ADLs), and complications of therapy. Medication reduction and improvements in life quality other than ADLs were not significantly different between LQ and VA/NINDS subjects. When the two populations were compared according to pre-DBS LDR, the “full responders” to levodopa (≥ 50% improvement on UPDRS-III with medication) in the two studies showed no significant difference in motor improvement with DBS (LQ 18.5 ± 12.0–point improvement on UPDRS-III vs VA/NINDS 17.7 ± 15.6–point improvement, p = 0.755). Among levodopa full responders, ADLs improved slightly more in the LQ group, but scores on other UPDRS subscales and the Parkinson’s Disease Questionnaire-39 were not significantly different between the two studies.

CONCLUSIONS

This comparison suggests that patient selection criteria, especially preoperative LDR, are the most important source of differences in motor outcomes and quality of life between the two studies.