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Jimmi Hatton, Richard Kryscio, Melody Ryan, Linda Ott and Byron Young

Object

Hypermetabolism, hypercatabolism, refractory nitrogen wasting, hyperglycemia, and immunosuppression accompany traumatic brain injury (TBI). Pituitary dysfunction occurs, affecting growth hormone (GH) and plasma insulin-like growth factor–I (IGF-I) concentrations. The authors evaluated whether combination IGF-I/GH therapy improved metabolic and nutritional parameters after moderate to severe TBI.

Methods

The authors conducted a prospective, randomized, double-blind study comparing combination IGF-I/GH therapy and a placebo treatment. Ninety-seven patients with TBI were enrolled in the study within 72 hours of injury and were assigned to receive either combination IGF-I/GH therapy or placebo. All patients received concomitant nutritional support. Insulin-like growth factor–I was administered by continuous intravenous infusion (0.01 mg/kg/hr), and GH (0.05 mg/kg/day) was administered subcutaneously. Placebo control group patients received normal saline solution in place of both agents. Nutritional and metabolic monitoring continued throughout the 14-day treatment period.

The two groups did not differ in energy expenditure, nutrient intake, or use of insulin treatment. The mean daily serum glucose concentration was higher in the treatment group (123 ± 24 mg/dl) than in the control group (104 ± 11 mg/dl) (p < 0.03). A positive nitrogen balance was achieved within the first 24 hours in the treatment group and remained positive in that group throughout the treatment period (p < 0.05). This pattern was not observed in the control group. Plasma IGF-I concentrations were above 350 ng/ml in the treatment group throughout the study period. Overall, the mean plasma IGF-I concentrations were 1003 ± 480.6 ng/ml in the treatment group and 192 ± 46.2 ng/ml in the control group (p < 0.01).

Conclusions

The combination of IGF-I and GH produced sustained improvement in metabolic and nutritional endpoints after moderate to severe acute TBI.

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Jimmi Hatton, Bonnie Rosbolt, Philip Empey, Richard Kryscio and Byron Young

Object

Cyclosporine neuroprotection has been reported in brain injury models but safety and dosing guidelines have not been determined in humans with severe traumatic brain injury (TBI). The purpose of this investigation was to establish the safety of cyclosporine using 4 clinically relevant dosing schemes.

Methods

The authors performed a prospective, blinded, placebo-controlled, randomized, dose-escalation trial of cyclosporine administration initiated within 8 hours of TBI (Glasgow Coma Scale score range 4–8; motor score range 2–5). Four dosing cohorts (8 patients treated with cyclosporine and 2 receiving placebo treatment per cohort) received cyclosporine (1.25–5 mg/kg/day) or placebo in 2 divided doses (Cohorts I–III) or continuous infusion (Cohort IV) over 72 hours. Adverse events and outcome were monitored for 6 months.

Results

Forty patients were enrolled over 3 years (cyclosporine cohorts, 24 male and 8 female patients; placebo group, 8 male patients). Systemic trough concentrations were below 250 ng/ml during intermittent doses. Higher blood concentrations were observed in Cohorts III and IV. There was no significant difference in immunological effects, adverse events, infection, renal dysfunction, or seizures. Mortality rate was not affected by cyclosporine administration, independent of dose, compared with placebo (6 of 32 patients receiving cyclosporine and 2 of 8 receiving placebo died, p > 0.05). At 6 months, a dose-related improvement in favorable outcome was observed in cyclosporine-treated patients (p < 0.05).

Conclusions

In patients with acute TBI who received cyclosporine at doses up to 5 mg/kg/day, administered intravenously, with treatment initiated within 8 hours of injury, the rate of mortality or other adverse events was not significantly different from that of the placebo group.

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John T. Slevin, Greg A. Gerhardt, Charles D. Smith, Don M. Gash, Richard Kryscio and Byron Young

Object. Glial cell line-derived neurotrophic factor (GDNF) has demonstrated significant antiparkinsonian actions in several animal models and in a recent pilot study in England in which four of five patients received bilateral putaminal delivery. In the present study the authors report on a 6-month unilateral intraputaminal GDNF infusion in 10 patients with advanced Parkinson disease (PD).

Methods. Patients with PD in a functionally defined on and off state were evaluated 1 week before and 1 and 4 weeks after intraputaminal catheter implantation in the side contralateral to the most affected side. Each patient was placed on a dose-escalation regimen of GDNF: 3, 10, and 30 µg/day at successive 8-week intervals, followed by a 1-month wash-out period.

The Unified Parkinson's Disease Rating Scale (UPDRS) total scores in the on and off states significantly improved 34 and 33%, respectively, at 24 weeks compared with baseline scores (95% confidence interval [CI] 18–47% for off scores and 16–51% for on scores). In addition, UPDRS motor scores in both the on and off states significantly improved by 30% at 24 weeks compared with baseline scores (95% CI 15–48% for off scores and 5–61% for on scores). Improvements occurred bilaterally, as measured by balance and gait and increased speed of hand movements. All significant improvements of motor function continued through the wash-out period. The only observed side effects were transient Lhermitte symptoms in two patients.

Conclusions. Analysis of the data in this open-label study demonstrates the safety and potential efficacy of unilateral intraputaminal GDNF infusion. Unilateral administration of the protein resulted in significant, sustained bilateral effects.

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Byron Young, Armin Shivazad, Richard J. Kryscio, William St. Clair and Heather M. Bush

Object

Despite the widespread use of Gamma Knife surgery (GKS) for trigeminal neuralgia (TN), controversy remains regarding the optimal treatment dose and target site. Among the published studies, only a few have focused on long-term outcomes (beyond 2 years) using 90 Gy, which is in the higher range of treatment doses used (70–90 Gy).

Methods

The authors followed up on 315 consecutive patients treated with the Leksell Gamma Knife unit using a 4-mm isocenter without blocks. The isocenter was placed on the trigeminal nerve with the 20% isodose line tangential to the pontine surface (18 Gy). At follow-up, 33 patients were deceased; 282 were mailed an extensive questionnaire regarding their outcomes, but 32 could not be reached. The authors report their analysis of the remaining 250 cases. The patients' mean age at the time of survey response and the mean duration of follow-up were 70.8 ± 13.1 years and 68.9 ± 41.8 months, respectively.

Results

One hundred eighty-five patients (85.6%) had decreased pain intensity after GKS. Modified Marseille Scale (MMS) pain classifications after GKS at follow-up were: Class I (pain free without medication[s]) in 104 (43.7%), Class II (pain free with medication[s]) in 66 (27.7%), Class III (> 90% decrease in pain intensity) in 23 (9.7%), Class IV (50%–90% decrease in pain intensity) in 20 (8.4%), Class V (< 50% decrease in pain intensity) in 11 (4.6%), and Class VI (pain becoming worse) in 14 (5.9%). Therefore, 170 patients (71.4%) were pain free (Classes I and II) and 213 (89.5%) had at least 50% pain relief. All patients had pain that was refractory to medical management prior to GKS, but only 111 (44.4%) were being treated with medication at follow-up (p < 0.0001). Eighty patients (32.9%) developed numbness after GKS, and 74.5% of patients with numbness had complete pain relief. Quality of life and patient satisfaction on a 10-point scale were reported at mean values (± SD) of 7.8 ± 3.1 and 7.7 ± 3.4, respectively. Most of the patients (87.7%) would recommend GKS to another patient. Patients with prior surgical treatments had increased latency to pain relief and were more likely to continue medicines (p < 0.05). Moreover, presence of altered facial sensations prior to radiosurgery was associated with higher pain intensity, longer pain episodes, more frequent pain attacks, worse MMS pain classification, and more medication use after GKS (p < 0.05). Conversely, increase in numbness intensity after GKS was associated with a decrease in pain intensity and pain length (p < 0.05).

Conclusions

Gamma Knife surgery using a maximum dose of 90 Gy to the trigeminal nerve provides satisfactory long-term pain control, reduces the use of medication, and improves quality of life. Physicians must be aware that higher doses may be associated with an increase in bothersome sensory complications. The benefits and risks of higher dose selection must be carefully discussed with patients, since facial numbness, even if bothersome, may be an acceptable trade-off for patients with severe pain.

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Roy A. Patchell, Yosh Maruyama, Phillip A. Tibbs, J. Lawrence Beach, Richard J. Kryscio and A. Byron Young

✓ Fifty-six patients with malignant glioma were treated with implantation of the neutron-emitting element californium-252 (252Cf) within 2 weeks after surgical debulking of the tumor. Implantation was performed using computerized tomography-guided placement of afterloading catheters, and the 252Cf sources were removed after approximately 300 neutron rads were delivered. Patients then received 6000 to 7000 conventional photon rads by external beam. The total photon-equivalent dose to the tumor ranged from 8100 to 9100 rads. The median survival time was 10 months, with 18- and 24-month survival rates of 28% and 19%, respectively. The results of reoperation or autopsy showed that patients had recurrence of the tumor but that radiation necrosis was restricted to the area of the original tumor. Serious complications occurred in five patients (9%) and consisted of wound infections in three, cerebral edema in one, and radiation necrosis beyond the original tumor margin in one.

Previous studies using external-beam neutron radiation have shown that neutrons are capable of totally eradicating malignant gliomas; however, in most cases, unacceptable widespread radiation necrosis has resulted. Neutron implants are a logical way to increase the dose to the tumor and decrease the dose to normal brain. Interstitial neutron radiation can be given safely with 252Cf, and the survival results achieved by radiation alone using relatively low doses of interstitial neutron radiation from 252Cf implants plus conventional photon radiation were equal to the results attained with any currently available conventional therapy.

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John T. Slevin, Don M. Gash, Charles D. Smith, Greg A. Gerhardt, Richard Kryscio, Himachandra Chebrolu, Ashley Walton, Renee Wagner and A. Byron Young

Object

Glial cell line–derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated.

Methods

During the extended study period, patients received a 30-μg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 μl/hour.

The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing.

Conclusions

The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.

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John T. Slevin, Don M. Gash, Charles D. Smith, Greg A. Gerhardt, Richard Kryscio, Himachandra Chebrolu, Ashley Walton, Renee Wagner and A. Byron Young

Object

Glial cell line–derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months was previously shown to improve motor functions and quality of life measures significantly in 10 patients with Parkinson disease (PD) in a Phase I trial. In this study the authors report the safety and efficacy of continuous treatment for 1 year or more. After the trial was halted by the sponsor, the patients were monitored for an additional year to evaluate the effects of drug withdrawal.

Methods

During the extended study, patients received unilateral intraputaminal infusion of 30 μg/day GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 μl/hour.

The Unified PD Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38%, respectively, in the “off” and “on” states. Motor UPDRS scores were also improved: 45 and 39% in the off and on conditions, respectively. Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted. At that time, the patients had returned to their baseline UPDRS scores and required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of the risk of infection. In seven patients antibodies to GDNF developed, with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing.

Conclusions

Unilateral administration of GDNF results in significant, sustained bilateral benefits. These improvements are lost within 9 months after drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.