Health related quality of life in patients with Parkinson's disease two years following posteroventral pallidotomy.

BACKGROUND: There has been a new emphasis on the use of health related quality of life (HRQOL) measures for translating how a patient's response to treatment is experienced by the patient. The purpose of this study was to describe patient reported HRQOL two years after surgery in subjects who underwent posteroventral pallidotomy (PVP) for the treatment of Parkinson's disease (PD) and a subset of these same subjects four years following PVP. METHOD: A consecutive series of 52 subjects who were evaluated previously, prior to and at 4 months following PVP [3], received long term follow-up using mailed questionnaires. Twenty seven subjects (52% of the original sample) provided 2 year follow-up data and 15 of these subjects (29%) provided 4 year follow-up data. Severity of disease and subject reported HRQOL were evaluated. FINDINGS: Immediately following surgery, there was a sharp decrease in all measures of severity of disease. While there were differing patterns of increasing severity of disease among the measures following the immediate postoperative assessment, all of the measures remained better than the pre-surgery values. The data showed a pattern of marked improvement in HRQOL at 4 months following PVP. Over the 2 years following surgery, there was a gradual deterioration toward preoperative levels that nevertheless remained better than preoperative HRQOL. For the group with data at 4 years following surgery, there was no significant further deterioration in HRQOL between 2 and 4 years, with the 4 year data also remaining better than the preoperative HRQOL reports. CONCLUSIONS: In spite of advanced severe PD and advanced age, subjects in this study reported better HRQOL at 2 years following PVP than they reported at entry into the study prior to surgery. Additionally, the 15 patients who were available for follow-up at 4 years also reported better HRQOL than they experienced prior to the surgery.

Pericapillary arteriovenous malformations angiographically manifested as cerebral venous malformations.

Cerebral venous malformations have been diagnosed by angiographic features and are considered to be a benign anomaly. However, ample evidence indicates that stroke or similar symptomatology occurs in patients harboring a cerebral vascular malformation that was diagnosed angiographically as a venous malformation. The purpose of the study is to confirm the presence of a pericapillary arteriovenous malformation in these patients by analyzing the clinical history and surgical findings and correlating them with histological features. Thirteen patients were included in this study. Each patient fulfilled four criteria: 1. the patient was neurologically symptomatic; 2. the angiographic diagnosis was a venous malformation; 3. at operation, shunting arterioles (50-100 microns) were found to contribute to the malformation; and 4. histologically, a mixture of venous channels and arterioles with arterioles directly connected to venules was found. Based on the above findings, the malformation present in the 13 patients can be termed a 'pericapillary arteriovenous malformation'. Its angiographic distinction from the cerebral venous malformation requires technological advancement in the capability of magnifying images of arterioles and venules, along with improvement in image resolution.

Detection of GDNF secretion in glial cell culture and from transformed cell implants in the brains of live animals.

Current ex vivo gene therapy for Parkinson's disease using glial cell line-derived neurotrophic factor (GDNF) is limited by the lack of a monitoring mechanism to determine the expression of GDNF once the cells or other vehicles are transferred into animal models. The purpose of this study was to test whether a Renilla luciferase (RUC)-GDNF fusion protein secreted by the genetically engineered glial cell line RG-1 could be measured photometrically in cerebrospinal fluid (CSF). RG-1 was constructed by permanent transformation with a plasmid DNA construct that contains a GDNF cDNA (gdnf) fused to a RUC cDNA (ruc). The fusion protein secreted by RG-1 was shown to retain both GDNF and RUC activity. The concentration of GDNF determined by enzyme-linked immunoadsorbent assay (ELISA) was correlated with the light emission detected by assaying for RUC bioluminescence in RG-1 culture medium, indicating that RUC can be used as a reporter for GDNF in vitro. The cells were then implanted into rat brain (n=20), and the cisternal CSF was analyzed. Bioluminescence was successfully detected in the CSF samples, and was quantified over a period of 25 days, while Western blotting and ELISA failed to detect GDNF in CSF, presumably because the concentration of the RUC-GDNF fusion was too low. This study demonstrates that the transformed glial cell line RG-1 offers a sensitive self-reporting assay for GDNF expression.

Changes in health related quality of life in patients with Parkinson's disease with and without posteroventral pallidotomy.

Traditional clinical outcome measures for the treatment of Parkinson's disease (PD) have focused on motor function and activities of daily living. However, in the past decade there has been a new emphasis on the use of health related quality of life (HRQOL) measures for translating how a patient's response to treatment is experienced by the patient. The purpose of this study was to describe patient reported HRQOL in subjects who underwent Posteroventral pallidotomy (PVP) for the treatment of PD compared with a similar group of subjects who did not undergo surgery (non-PVP). A consecutive series of patients who underwent PVP (n = 52) was compared prospectively with a similar group of patients, who received adjustments to medications without surgery (n = 45). Severity of disease and self reported HRQOL were evaluated at two time periods. Time 1 data were collected within one week prior to surgery for the PVP group or when subjects received medication adjustments for the non-PVP group. Time 2 data were collected 4 months later. Results showed that the severity of disease improved from Time 1 to Time 2 for both groups. HRQOL improved significantly for the PVP group (p = 0.001) but not for the non-PVP group (p > 0.29). Changes in HRQOL were most strongly related to the improvement in severity of disease in the "off" state. The results of this study suggest that PVP is associated with significant improvements in clinical and patient reported outcomes four months following surgery compared with a similar group of patients who did not undergo surgery. Additionally, the results suggest that the difference in perceived outcome between the groups is due in part to the improvement in the levodopa "off" periods which occurred for the PVP group but not for the non-PVP group.

Serotonergic decompensation in the akinetic expression of Parkinson's disease.

The current diagnostic and treatment paradigm for the akinetic form of Parkinson's disease asserts that the majority of symptoms and treatment phenomena arise from a dysfunctional dopaminergic system. Recent studies have attempted to determine the roles of other biogenic amine neurotransmitters such as serotonin and norepinephrine. Metabolic breakdown product studies of Parkinsonian and non-Parkinsonian cerebrospinal fluid (CSF) samples indicate significant differences in the levels of serotonin and norepinephrine in addition to the levels of dopamine. Such changes may suggest that current pharmacologic therapies that attempt to restore only dopamine are inadequate, and require accompanying therapies to elevate serotonin and norepinephrine levels.

Electrophysiological versus image-based targeting in the posteroventral pallidotomy.

OBJECTIVE: To study the functional accuracy of stereotactic targeting for the posteroventral pallidotomy (PVP), comparing targets chosen on magnetic resonance images (MRI), and fused MRI to computed tomographic (CT) images, with electrophysiologically refined anatomical targets. METHDOS AND MATERIALS: For each of the 10 pallidotomies three sets of targets were collected, beginning with the MRI targets. The second target set was measured on images generated by nonlinear volumetric fusion of MRI images with CT using Image Fusion (Radionics, Inc.). The anatomical target site was then determined electrophysiologically with intraoperative microelectrode recording and macroelectrode stimulation guidance. RESULTS: Magnetic resonance imaging or MRI-CT fused images alone would not have been sufficiently accurate to preclude visual or motor complications in the posteroventral pallidotomy, based on our target located within 1 mm of the optic tract and within 2 mm of the internal capsule. In 2 of the 10 cases of either MRI or fused images, the targets were dangerously close to the optic tract. Two of 10 of the fused targets were within the internal capsule. The fusion of MRI with CT did not functionally improve the targeting accuracy of MRI, since the means of the MRI targets and the fused targets were statistically the same. Individually, however, the MRI target was different from the fused target in each case by an average radial distance of 3.5 +/- 2.3 mm, but such corrections were not statistically or surgically significant. CONCLUSIONS: Image-based targeting including MRI or fused MRI-CT data may not be sufficiently accurate to prevent capsular or visual deficits in the posteroventral pallidotomy, necessitating electrophysiological refinement. In this report, the functional accuracy of MRI was not improved by fusion with CT.

Endoscopic procedures for resection of arteriovenous malformations.

BACKGROUND: Resection of arteriovenous malformations (AVMs), particularly those located in functional areas, requires precision. To enhance that precision, endoscope-assisted microsurgery has been employed at Loma Linda University. METHODS: Twenty-five consecutive cases of AVM were treated microsurgically with endoscopic assistance. Patients were divided into two groups: (1) those having AVMs in functional areas, and (2) those whose AVMs extended into the ventricle, either in the trigonal area or the capsulocaudatothalamic area. The endoscope was inserted into the subarachnoid space to interrupt communicating venules around the major draining vein and into the cleavage developed between the AVM venous loops and surrounding brain tissue as shunting arterioles and communicating venules were interrupted. For surgery of intraventricular AVMs, the curved endoscope was inserted into the ventricle, providing visualization of the AVM core, which was dissected from the ventricular side. RESULTS: AVMs were totally resected in all cases except for two patients with capsulocaudatothalamic AVMs, which were decreased in size sufficiently to receive radiosurgery. CONCLUSION: Endoscope-assisted microsurgery enhances magnification, illumination, and technical precision while the surgeon is dissecting the AVM core vessels and while operating on AVMs extending into the ventricle.

Regional metabolic changes in the pedunculopontine nucleus of unilateral 6-hydroxydopamine Parkinson's model rats.

The pedunculopontine nucleus (PPN) located in the mesopontine tegmentum is innervated by descending projections from nuclei in the basal ganglia. The present study was performed to determine whether nigrostriatal dopaminergic neuron degeneration is associated with changes in PPN metabolic activity. Unilateral nigrostriatal lesioning was performed by injecting 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta in 10 rats. Six of these animals exhibited apomorphine-induced rotations contralateral to the lesion and were included in the experimental group for determination of regional cerebral metabolic rate for glucose (rCMRglucose) along with five sham-lesioned and five normal controls. All studies were performed 13-15 days after lesioning using [14]C-2-deoxyglucose autoradiography. Significant hemispheric differences in metabolic activity were observed only in the 6-OHDA lesioned animals. Increased rCMRglucose was found in the globus pallidus (+63%) ipsilateral to the lesion as compared to the contralateral hemisphere, and reduced rCMRglucose in the primary motor, sensory, and auditory cortex (-7%, -12% and -7%, respectively), and in the subthalamic nucleus (-6%). Metabolic activity within the PPN ipsilateral to the lesion was significantly greater than the contralateral hemisphere (P<0.05; lesion 57+/-8, nonlesion 52+/-5), and significantly greater than the sham-lesioned side of the sham rat (P<0.05; sham lesion 47+/-5). No hemispheric differences were observed in the lateral dorsal tegmental nucleus. These observations offer further support for a role of the PPN in Parkinson's and for the utility of the rodent unilateral 6-OHDA model in defining the pathophysiologic significance of the mesopontine tegmental striatal-motor interfaces in basal ganglia disease.

A comparative study on neurochemistry of cerebrospinal fluid in advanced Parkinson's disease.

This study addresses two issues: (1) the comparative neurochemistry of classic tremor type of Parkinson's disease or PD-A and akinetic type of Parkinson's disease or PD-B; and (2) the neurochemistry of levodopa failure syndrome (LDFS). Cerebrospinal fluid from the lateral ventricle was collected from 50 patients with idiopathic Parkinson's disease of PD-A and PD-B. Levels of monoamine neurotransmitters and metabolites were determined using high performance liquid chromatography. We have found that (1) 5-hydroxylindoleacetic acid (5-HIAA) level is significantly lower in PD-B than in PD-A; (2) 5-HIAA level is inversely associated with score of part one of United Parkinson's Disease Rating Score (UPDRS); (3) 5-HIAA level is inversely associated with score of part four of UPDRS; (4) 3-O-methyldopa (3-OMD) level is positively associated with levodopa failure syndrome (LDFS) assessed by part four of UPDRS and inversely associates with 5-HIAA. From these data, it can be inferred that serotonergic activity is decreased in PD-B to a greater extent than in PD-A and that decreased serotonergic activity plays a role in LDFS.

Clinical application of ketamine ointment in the treatment of sympathetically maintained pain.

The objective of this study was to determine the clinical efficacy of topical ketamine in relieving sympathectically maintained pain, including complex regional pain syndrome types I and II, involving the upper and/or lower extremities. In an open clinical pilot study of five referral patients diagnosed with sympathetically maintained pain who were unresponsive to conventional modalities, a single dose of topical ketamine was administered. Age, gender, duration or degree of disease and concurrent medication were not controlled. Ketamine was prepared for transdermal delivery in pluronic lethicin organogel (PLO) in calibrated applicators. Concentrations ranged from 10 to `50 mg/mL. Dosage ranged from 10 mg to 700 mg per single application. Each dosage was deternined clinically based on location and suface area of involvement. Pain intensity was measured using a validated mumeric analogue scale (NAS). Ketamine in PLO applied to the uper and/or lower extremities with sympathetically maintained pain resulted in significant pain reduction relative to pretreatment NAS of 65% to 100% . Initial response was within 20 seconds to three minutes, with NAS rating 15 minutes postapplication. No reported side effect occurred on patient follow-up at 24 and 48 hours. Single-dose, topical application of ketamine in PLO (patent pending) appears clinically effective in relieving sympathetically maintained pain of the extremities without apparent side effects. Further controlled studies are warranted to define patient selection, optimize dosage and validate the prominent analgesic effects obtained in this heretofore difficult-to-treat pain syndrome. This was an independent study in joint cooperation with representatives from the Univesity of California at Irvine, Loma Linda University Medical Center and private practice.

Contemporaneous bilateral pallidotomy.

To investigate the effects of bilateral posteroventral pallidotomy (PVP) for Parkinson's disease (PD), the authors reviewed the technique and neurological outcome in a number of patients who had undergone bilateral pallidotomy. The authors have previously reported the outcome of PVP in 25 bilateral and 25 unilateral surgeries, rating the patient's postural stability, speech, and total Unified Parkinson's Disease Rating Scale scores. A second, separate group of 23 patients who underwent contemporaneous bilateral PVP were evaluated for early onset idiopathic PD, levodopa failure syndrome, and severe bilateral dyskinesia as well as akinetic "off" states. Cognitive and psychological studies were reviewed in 10 patients who demonstrated preoperative impairments in spatial recognition and memory. Following surgery there were significant improvements in these cognitive deficits and no deficits were incurred by surgery. Published reports regarding bilateral operations for PD have emphasized the risks of speech and cognitive deficits. This study shows bilateral PVP to be effective, particularly in patients with bilateral symptoms, including disabling dyskinesia. Additionally, bilateral PVP does not cause additional cognitive or speech deficits. The techniques and indications as well as outcomes and complications are presented and discussed in this report in light of their controversial nature.

Concentrations of indoleamine metabolic intermediates in the ventricular cerebrospinal fluid of advanced Parkinson's patients with severe postural instability and gait disorders.

Postural instability and gait disorders (PIGD) are the primary causes of disability in many but not all advanced Parkinson's disease (PD) patients. We have measured the concentrations of serotonin, 5-hydroxytryptophan (5-HTP), 5-hydroxy-3-indoleacetic acid (5-HIAA), and homovanillic acid (HVA) in samples of ventricular cerebrospinal fluid from ten PD patients with severe disability from PIGD and from ten PD patients with tremor and levodopa induced dyskinesia as their predominant motor dysfunction. The two groups were prospectively matched for duration of disease and age. No significant differences between the two groups were found in the concentration (mean +/- SD in ng/ml, PIGD dominant vs. tremor-dyskinesia dominant) of 5-HIAA (106 +/- 50 vs. 99 +/- 34) or HVA (1,068 +/- 595 vs. 881 +/- 469). Serotonin concentration was significantly lower (0.7 +/- 0.5 vs. 1.5 +/- 0.9) and 5-HTP concentration was substantially higher (684 +/- 1,054 vs. 6 +/- 5) in the patient group with PIGD as their predominant symptoms. Thus, the distinguishing feature of patients with severe PIGD appears to be a derangement in indoleamine metabolism at the reaction step catalyzed by aromatic amino acid decarboxylase (AADC). These findings suggest that aggravation of PIGD in advanced Parkinson's may be related in part to impaired serotonergic transmission secondary to inhibition or down regulation of AADC.

Electrophysiologic target localization in posteroventral pallidotomy.

The current interest in stereotactic posteroventral pallidotomy (PVP) for treating Parkinson's disease and the variability of published results have raised questions regarding techniques for target localization. In our technique the probe is guided to the optimum target at the most ventral pallidum and ansa lenticularis by macroelectrode stimulation of the internal capsule and optic tract from within the globus pallidus, with the thresholds providing a relative measure of the electrode proximity to these structures. We have characterized these localizing macroelectrode stimulation parameters in 57 posteroventral pallidotomies with consistent anatomic lesion placement, excellent outcome, and no complications. Using a 1.8 x 2.0 mm radiofrequency electrode for macroelectrode stimulation (RFG-3C, Radionics Inc.), minimum voltages (thresholds) to activate motor (at a frequency of 2 Hz) or visual (at a frequency of 100 Hz) responses as well as impedance measurements were obtained at the final target (Tf) and at distances proximal to Tf along the electrode trajectory. The visual and motor threshold voltages at Tf via our standard approach angles (50 degrees above base plane, 20 degrees from the sagittal plane), had a range of 1.0 to 1.5 V, and 2.0 to 3.5 V respectively. We also found that as the probe approaches Tf there is a significant decrease in voltage thresholds for motor (P < .0001) and visual (P < .0001) responses in an individual patient indicating that the probe is converging on these structures. Increases in impedance between Tf, 2-3 mm, and 4-5 mm proximal to Tf were also statistically significant (P < .0001). Microelectrode recording to electrophysiological neuronal activity at various points along the trajectory towards the target showed distinct firing patterns providing identification of the globus pallidus externus and internus, ansa lenticularis, and optic tract. Macroelectrode electrophysiological stimulation within the target volume, inducing threshold responses in the internal capsule and optic tract, provides for accurate localization of the most effective PVP target in the ansa lenticularis. In unresponsive patients, the utilization of microelectrode recording for the identification of the pallidal borders and the optic tract improves safety.

Gamma knife pallidotomy: case report.

We report a case of gamma knife pallidotomy resulting in a permanent contralateral homonymous hemianopsia and transient contralateral hemiparesis with some improvement in contralateral parkinsonian symptoms. This case illustrates the risk of gamma knife pallidotomy which precludes physiologic target localization and can subject structures surrounding the target to a significant radiosurgical dose. Until noninvasive physiologic target localization is available gamma knife pallidotomy and thalamotomy should be limited to patients with an unacceptably high risk for stereotactic percutaneous thermocoagulation.

Normalization of middle latency auditory P1 potential following posterior ansa-pallidotomy in idiopathic Parkinson's disease.

The P1 potential (50 msec) of middle latency auditory evoked potential was evaluated in seven patients with advanced idiopathic Parkinson's disease before and after contemporaneous bilateral posterior ansa-pallidotomy. P1 potential was lacking in two patients preoperatively and was prolonged in the remainder of the patients when examined in a best medicated 'on' state. All patients showed varying degrees of dementia preoperatively on clinical examination. Remarkable improvement in their Unified Parkinson's Disease Rating Scale (UPDRS) scores during 'on' states from a mean of 45.85 to 14.28 post-operatively was achieved. Subsidence of akinetic symptoms, abolishment of dyskinesia, improvement in gait freezing, rigidity, and tremors represented main areas of improvement. P1 latencies and amplitudes reverted back to normal values in six patients including the two patients who lacked P1 wave preoperatively. One patient showed mild worsening of both Pa and P1 values post-operatively attributed to sleepiness during testing, a transient phenomenon commonly encountered following posterior ansa-pallidotomy. The post-operative P1 changes were statistically significant for both latencies and amplitudes at p = 0.078 and p = 0.073, respectively, for all seven patients using one tailed paired t-test. The change in UPDRS post-operatively best correlated with the post-operative difference in P1; specifically, UPDRS subscore II with P1 amplitude (r = -0.068, p = 0.09), and UPDRS subscore IV with Pa: P1 ratio (r = +0.77, p = 0.04). Earlier clinical and experimental work support the tegmental pedunculopontine nucleus (PPN) as the site of origin of P1 wave. In addition, its presence reflects the integrity of output cholinergic projection from PPN to both ascending reticular activating system ARAS and auditory pathway. We believe this is the first report of restoring the integrity of P1 wave following posterior ansa-pallidotomy in patients with advanced idiopathic Parkinson's disease. Disinhibition of the PPN by posterior ansa-pallidotomy can explain improvements in motor symptoms in view of reemergence and normalization of P1 wave form.

Bypass coaptation procedures for cervical nerve root avulsion.

In the past, patients with cervical spinal nerve root avulsions were resigned to accept a natural crippling from upper extremity neurological deficits. Recently, bypass coaptation procedures have resulted in functional return of denervated muscles after such avulsions, much to the appreciation of patients. Presented are 12 patients with avulsion of cervical spinal nerve roots that form either the brachial plexus upper trunk (n = 7), lower trunk (n = 1), or all three trunks (n = 4). The patients underwent the new bypass coaptation procedures with complete or partial return of motor and sensory function, which otherwise would be totally nonfunctional. The most dramatic results were noted in those patients who underwent operations within 6 weeks of injury. The results of these procedures offer patients a valid therapeutic modality for an enhanced quality of life after cervical nerve root avulsion.

Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans.

A 17-year-old Russian male with a 9-year diagnosed history of dystonia musculorum deformans manifested as severe tortipelvis, lordosis, and axial and appendicular spastic dystonia, refractory to medical therapy, is reported. This patient underwent a simultaneous bilateral pallidoansotomy with dramatic results. Postoperative evaluation revealed sustained alleviation of all dystonic symptoms and abnormal movements. Rapid recovery of useful strength in all limbs as well as dramatic improvement in coordination occurred. Bilateral posteroventral pallidotomy and pallidoansotomy in the past have proven effective in alleviation of all parkinsonian symptoms, including dyskinesia and dystonia, without the concurrent risk of intransigent side effects associated with bilateral thalamotomy or other stereotactic surgical procedures. Pallidoansotomy may prove to be the treatment of choice for idiopathic torsion dystonia and merits further investigation.