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Objective. The conventional technique used to stimulate the lumbar dermatomes is by stimulation of the dorsal columns of the spinal cord. Until recently, stimulation of nerve roots had not been successfully accomplished. We had performed selective nerve root cannulations for the placement of temporary catheters at cervical, thoracic, lumbar, and sacral levels in chronic pain patients using a caudad rather than craniad approach. We hypothesized that by stimulating the nerve roots we could improve paresthesia coverage in areas which cannot be covered effectively by spinal cord stimulation (SCS). To test this hypothesis, we have performed trials of nerve root stimulation (NRS) in patients who had failed SCS, or who were not candidates for SCS because their pain was otherwise inaccessible to stimulation. Methods. Five patients who had been unresponsive to conservative treatment, surgery, or SCS underwent 7-day trials with NRS. The diagnoses included: ilioinguinal neuralgia, discogenic low back pain, failed back syndrome, vulvodynia, and interstitial cystitis. We collected paresthesia maps, pain maps, pain visual analog scale (VAS) scores, and patient satisfaction ratings. Results. Paresthesia coverage was above 75% in all patients. VAS scores declined from a mean of 9 ± 1.0 to 2.4 ± 2.1 (p < 0.05, n= 5), all 5 patients requested permanent implantation, and 4 have been implanted so far. Conclusions. Lumbar and sacral NRS trials resulted in adequate paresthesia coverage and effective pain relief in all 5 patients. Further clinical trials to evaluate long-term success rates and safety are indicated. Detailed mapping studies are needed to evaluate the relationship between electrode placement and paresthesia patterns as well as the optimal stimulation parameters.

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Objective. To evaluate effectiveness of spinal cord stimulation (SCS) applied to complex regional pain syndrome I (CRPS I). To analyze trends to focus the design of a multicenter prospective study. Design. Retrospective multicenter series, 3 years. Outcome measures. We collected visual analog scales for pain and patient satisfaction data on n= 101 patients. Patients were divided into two groups: Group I had single-lead quadrapolar systems, Group II had dual-lead octapolar systems. Results. Mean pain scores decreased in both groups with a significantly greater decrease in Group II (p < 0.0001). 74.6% of Group II patients preferred multiple programming arrays with 15.5% requiring frequencies > 250Hz.; overall satisfaction scores were 70% in Group I and 91% in Group II (p < 0.05). Conclusions. SCS is an effective treatment of pain in CRPS I. Frequencies > 250Hz were necessary in some patients to maintain or re-establish pain control. Bilateral multielectrode leads appear superior with application of multiple arrays, permitting paresthesia steering without need for surgical revision. A multicenter, prospective design is needed applying dual-lead multichannel systems with high frequency capabilities in the treatment of CRPS I.

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Objective. Since 1996 we have placed temporary catheters at the cervical nerve roots in chronic pain patients for the treatment of radiculopathy and complex regional pain syndrome. We investigated the possibility of placing electrodes both at the cervical spinal nerve and dorsal root ganglion for the purpose of neuromodulation. Methods. Anatomic and technical feasibility studies were performed on 4 human cadavers to examine the placement of electrodes at the cervical nerve roots. We proposed a novel trans-spinal approach to the cervical and upper thoracic nerve roots. We tested various approaches and insertion techniques. We collected radiographic images of the essential steps involved in this technique. Results. Successful placement was accomplished in 3 of the 4 cadavers at the C3, C4, C5, C6, C7, C8, T1, and T2 nerve roots. For placement at C5 to T2, we used a trans-spinal approach entering at the corresponding contralateral interlaminar space. However, due to the anatomy of the cervical nerve roots, vertebral artery, cervical plexus, and occiput, it was necessary to use a different technique for the upper cervical nerve roots. For placement at the C3 and C4 nerve roots, we made the initial insertion between the C1 and C2 lamina using curved needles which were advanced in a caudal direction transversing the median plane of the spine to arrive at the contralateral inter vertebral foramen of either C3 or C4. We were unable to cannulate either C1 or C2 in any of the cadavers. The required equipment included fluoroscopy, contrast dye, directable guide wires, electrodes, and curved needles. Conclusions. In human cadavers, a percutaneous technique was successful in the placement of neurostimulator electrodes at the cervical and upper thoracic nerve roots using a novel trans-spinal approach. New smaller electrode systems that can be placed in a transforaminal position safely may be needed.

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The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.

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STUDY OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration. DESIGN: Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. SETTING: Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. PATIENTS: Neurosurgical patients who required anticonvulsant prophylaxis or treatment. INTERVENTIONS: In the intramuscular study, 118 patients received loading doses ranging from 480-1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130-1250 mg PE for 3-14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3-14 days. Mean +/- SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 +/- 299 mg PE and 411 +/- 221 mg PE, and 1082 +/- 299 mg and 422 +/- 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients. MEASUREMENTS AND MAIN RESULTS: Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p < 0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 micrograms/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days. CONCLUSION: Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.

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A retrovirus which encodes beta-galactosidase was used to infect embryonic rat striatal cells before grafting these cells into the lesioned adult rat striatum. Examination of the grafts after long term survival (8 months) revealed that a few small and large cells expressed large amounts of bacterial beta-galactosidase activity. The larger diameter cells were identified as neurones by their size, shape and presence of neuronal processes. The identity of the small diameter cell types was not established.

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