Valerie C. Anderson

Comparison of Pallidal and Subthalamic Nucleus Deep Brain Stimulation for Advanced Parkinson's Disease: Results of a Randomized, Blinded Pilot Study

OBJECTIVE Deep brain stimulation (DBS) of the globus pallidus internus (GPi) and subthalamic nucleus (STN) has been reported to be effective in alleviating the symptoms of advanced Parkinsons disease (PD). Although recent studies suggest that STN stimulation may be superior to GPi stimulation, a randomized, blinded comparison has not been reported. The present study was designed to provide a preliminary comparison of the safety and efficacy of DBS at either site. METHODS Ten patients with idiopathic PD, L-dopa-induced dyskinesia, and response fluctuations were randomized to implantation of bilateral GPi or STN stimulators. Neurological condition was assessed preoperatively with patients on and off L-dopa and on DBS at 10 days and 3, 6, and 12 months after implantation. Patients and evaluating clinicians were blinded to stimulation site throughout the study period. Complete follow-up data were analyzed for four GPi patients and five STN patients. RESULTS When off-L-dopa, both GPi and STN groups demonstrated a similar response, with approximately 40% improvement in Unified PD Rating Scale motor scores after 12 months of DBS. Rigidity, tremor, and bradykinesia improved in both groups. In combination with L-dopa, Unified PD Rating Scale motor scores were more improved by GPi stimulation than by STN stimulation. On-L-dopa axial symptoms were clinically improved in the GPi but not the STN group. L-Dopa-induced dyskinesia was reduced by DBS at either site, although medication requirement was reduced only in the STN group. There were no serious intraoperative complications among patients in either group. CONCLUSION Pallidal and STN stimulation appears to be safe and efficacious for the management of advanced PD. A larger study is needed to investigate further the differences in symptom response and the interaction of L-dopa with stimulation at either site.

Prospective, multicenter study of spinal cord stimulation for relief of chronic back and extremity pain.

Study Design This prospective, multicenter study was designed to investigate the efficacy and outcome of spinal cord stimulation using a variety of clinical and psychosocial outcome measures. Data were collected before implantation and at regular intervals after implantation. This report focuses on 70 patients who had undergone 1 year of follow‐up treatment at the time of data analysis. Objectives To provide a more generalizable assessment of long‐term spinal cord stimulation outcome by comparing a variety of pain and functional/quality‐of‐life measures before and after management. This report details results after 1 year of stimulation. Summary of Background Data The historically diverse methods, patient selection criteria, and outcome measures reported in the spinal cord stimulation literature have made interpretation and comparison of results difficult. Although short‐term outcomes are generally consistent, long‐term outcomes of spinal cord stimulation, as determined by prospective studies that assess multidimensional aspects of the pain complaint among a relatively homogeneous population, are not well established. Methods Two hundred nineteen patients were entered at six centers throughout the United States. All patients underwent a trial of stimulation before implant of the permanent system. Most were psychologically screened. One hundred eighty‐two patients were implanted with a permanent stimulating system. At the time of this report, complete 1‐year follow‐up data were available on 70 patients, 86% of whom reported pain in the back or lower extremities. Patient evaluation of pain and functional levels was completed before implantation and 3, 6, 12, and 24 months after implantation. Complications, medication usage, and work status also were monitored. Results All pain and quality‐of‐life measures showed statistically significant improvement during the treatment year. These included the average pain visual analogue scale, the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Sickness Impact Profile, and the Beck Depression Inventory. Overall success of the therapy was defined as at least 50% pain relief and patient assessment of the procedure as fully or partially beneficial and worthwhile. Using this definition, spinal cord stimulation successfully managed pain in 55% of patients on whom 1‐year follow‐up is available. Complications requiring surgical intervention were reported by 17% (12 of 70) of patients. Medication usage and work status were not changed significantly. Conclusions This prospective, multicenter study confirms that spinal cord stimulation can be an effective therapy for management of chronic low back and extremity pain. Significant improvements in many aspects of the pain condition were measured, and complications were minimal.

A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain.

OBJECTIVE To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities. METHODS Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored. RESULTS The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients. CONCLUSION Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function.

Prognostic factors of spinal cord stimulation for chronic back and leg pain.

Spinal cord stimulation (SCS) has been used for more than 20 years in the treatment of diverse pain conditions. Although recent studies have identified more clearly those conditions for which SCSoffers a favorable prognosis, the identification of a patient population in whom reasonably long-term success can be expected has been difficult. In an effort to improve patient selection and increase the overall success rate of treatment, we have examined various physical, demographic, and psychosocial variables as predictors of SCS outcome. The study population consisted of 40 patients with chronic low back and/or leg pain, 85% of whom were diagnosed with failed back surgery syndrome. Medical history and demographic data were collected as part of an initial assessment along with patient responses to the Minnesota Multiphasic Personality Inventory, the visual analogue pain rating scale (VAS), the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Beck Depression Inventory, and the Sickness Impact Profile. Treatment outcomes were examined and found to improve significantly after 3 months of stimulation. Subsequent regression analysis revealed that patient age, the Minnesota Multiphasic Personality Inventory depression subscale D, and the evaluative subscale of the McGill Pain Questionnaire (MPQe) were important predictors of posttreatment pain status. Increased patient age and D subscale scores correlated negatively with pain status, as measured by the percentage of changes in pretreatment and posttreatment VAS scores, % delta VAS. In contrast, higher MPQe correlated with improved pain status. By the use of the following equation and the definition commonly associated with SCS success (at least 50% decrease in the VAS pain level), the success or failure of 3 months of SCS was correctly predicted in 88% of the study population. Our results suggest that patient age, Minnesota Multiphasic Personality Inventory depression, and MPQe may be clinically useful in the prediction of pain status after 3 months of SCS in patients with chronic low back and/or leg pain. % delta VAS = 112.57 - 1.98 (D)-1.68 (Age) + 35.54 (MPQe).

High-resolution Three-dimensional Magnetic Resonance Angiography and Three-dimensional Spoiled Gradient-recalled Imaging in the Evaluation of Neurovascular Compression in Patients with Trigeminal Neuralgia: A Double-blind Pilot Study

OBJECTIVE:To assess the value of high-resolution three-dimensional (3D) time-of-flight (TOF) magnetic resonance (MR) angiography and gadolinium (Gad)-enhanced 3D spoiled gradient-recalled imaging in the visualization of neurovascular compression in patients with trigeminal neuralgia. METHODS:Forty-eight patients with unilateral trigeminal neuralgia underwent high-resolution 3D TOF MR angiography. After administration of a contrast agent, a 3D spoiled gradient-recalled sequence (3D Gad) was run. Images were reviewed by a radiologist blinded to clinical details. All patients underwent microvascular decompression surgery. Microdissection of the trigeminal nerve and compressing vessels was videotaped during surgery and reviewed by surgeons uninvolved in patient care. Results from neuroradiological studies were then compared with findings on operative videotapes. RESULTS:MR angiography in combination with 3D Gad imaging identified surgically verified neurovascular contact in 42 of 46 (91%) symptomatic nerves. The offending vessel (artery, vein) was correctly identified in 31 of 41 cases (sensitivity, 76%; specificity, 75%). Neurovascular compression was observed in 71% of asymptomatic nerves with a trend toward greater compression severity on the symptomatic nerve (P < 0.09). Agreement between the direction of neurovascular contact defined by 3D TOF MR angiography and 3D Gad and findings at surgery was good (&kgr; = 0.78; 95% confidence interval, 0.61–0.94). CONCLUSION:Double-blind assessment of surgical and neuroradiological findings confirms that neurovascular compression can be visualized with good sensitivity in patients with trigeminal neuralgia by 3D TOF MR angiography in combination with Gad-enhanced 3D spoiled gradient-recalled sequences. Anatomic relationships defined by this method can be useful in predicting surgical findings.

DBS and diathermy interaction induces severe CNS damage

Pulse-modulated radiofrequency diathermy treatment to the maxilla produced permanent diencephalic and brainstem lesions and a vegetative state in a patient with PD with implanted subthalamic electrodes for deep brain stimulation.

Interactions between deep brain stimulation and levodopa in Parkinson’s disease

Objective: To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. Background: Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. Methods: Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. Results: DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. Conclusion: DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

Long-term outcome following ilioinguinal neurectomy for chronic pain.

OBJECT Ilioinguinal neuralgia is one cause of chronic groin pain following inguinal hernia repair, and it affects approximately 10% of patients. Selective ilioinguinal neurectomy is one proposed treatment option for carefully selected patients. The goal of this study was to determine the long-term outcome of patients who underwent selective ilioinguinal neurectomy for chronic post-hernia pain. METHODS The authors retrospectively reviewed the clinical assessment, surgical treatment, and long-term outcome in 26 patients with ilioinguinal neuralgia who underwent selective ilioinguinal neurectomy performed by the senior author (K.J.B.) at Oregon Health & Science University between 1998 and 2008. Data were collected from patient charts and a follow-up telephone questionnaire. RESULTS Twenty-six patients (14 men and 12 women) had a clinical diagnosis of ilioinguinal neuralgia based on a history of radiating neuropathic groin, medial thigh, and genitalia pain. One patient had bilateral disease (therefore there were 27 surgical cases). A selective nerve block was performed in 21 (81%) of 26 patients and was positive in 20 (77%) of the 26. In all but 2 patients, pain onset followed abdominal surgery (for hernia repair in 18 patients), and was immediate in 16 (67%) of 24 patients. The mean patient age was 48.7 years, and the mean duration of pain prior to neurosurgical consultation was 3.9 years. Surgery was performed after induction of local or general anesthesia in 17 and 10 cases, respectively. The ilioinguinal nerve was identified in 25 cases, and the genitofemoral nerve in 2, either entrapped in mesh, scar, or with obvious neuroma (22 of 27 cases). The identified nerve was doubly ligated, cut, and buried in muscle at its most proximal point. At the 2-week follow-up evaluations, 14 (74%) of 19 patients noted definite pain improvement. Nineteen (73%) of the 26 patients were contacted by telephone and agreed to participate in completing long-term follow-up questionnaires. The mean follow-up duration was 34.78 months. Return of pain was reported by 13 (68%) of 19 patients. Using a verbal numerical rating scale (0-10), pain was completely relieved in 27.8%, better in 38.9%, no better in 16.7%, and worse in 16.7% of patients. CONCLUSIONS Ilioinguinal neurectomy is an effective and appropriate treatment for selected patients with iatrogenic ilioinguinal neuralgia following abdominal surgery. Although a high proportion of patients reported some long-term recurrence of pain, complete or partial pain relief was achieved in 66.7% of the patients observed.

Cyclin dependent kinase-5 (CDK-5) phosphorylates neurofilament heavy (NF-H) chain to generate epitopes for antibodies that label neurofilament accumulations in amyotrophic lateral sclerosis (ALS) and is present in affected motor neurones in ALS

1. Accumulations of phosphorylated neurofilaments are seen in affected motor neurones in amyotrophic lateral sclerosis (ALS). 2. The authors demonstrate that cyclin dependent kinase-5 (cdk-5) will induce cellular phosphorylation of neurofilament heavy chain side-arms to generate epitopes for several antibodies that label these neurofilament accumulations. 3. By creating recombinant neurofilament fragments of NF-H side-arm domains, the authors also map the epitopes for several of these antibodies. 4. Finally, the authors demonstrate that cdk-5 is also present in affected motor neurones in ALS. These studies implicate cdk-5 in the pathogenesis of ALS.

Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis

We have studied the distribution of cyclin dependent kinase-5 (cdk-5) within spinal cord in sporadic and two superoxide dismutase type 1 (SOD1) familial cases of amyotrophic lateral sclerosis (ALS). Although most neurofilament accumulations in ALS motor neurones did not appear to contain high levels of cdk-5, intense cdk-5 immunoreactivity was observed in perikarya of degenerating neurones in many ALS cases. Here, cdk-5 co-localised with lipofuscin. Co-localisation of cdk-5 with lipofuscin was also observed in some aged non-affected controls although this labelling was less intense than the ALS cases. The biogenesis of lipofuscin is believed to be linked to oxidative stress and oxidative stress and free radical damage have been suggested to be part of the pathogenic process of ALS, possibly involving apoptotic mechanisms. cdk-5 has recently been associated with apoptosis. These observations suggest a role for cdk-5 in the pathogenesis of ALS.