INTRAPUTAMINAL INFUSION OF NERVE GROWTH-FACTOR TO SUPPORT ADRENAL-MEDULLARY AUTOGRAFTS IN PARKINSONS-DISEASE - ONE-YEAR FOLLOW-UP OF 1ST CLINICAL-TRIAL

Experimental studies in rodents show that beta-nerve growth factor can increase the survival, neurite outgrowth, and functional effect of grafts of adrenal chromaffin cells to the basal ganglia. We, therefore, have begun to investigate whether treatment with nerve growth factor might also increase the functional effect of autografts of adrenal medullary tissue in patients with Parkinson's disease. Previous studies have shown that stereotactic implantation of adrenal tissue pieces produces a transient functional improvement that lasts for a few months. This report describes a trial of grafting of adrenal chromaffin tissue into the putamen, supported by infusion of nerve growth factor. The patient is a 63-year-old woman with a 19-year history of Parkinson's disease, now complicated by on-off phenomena and drug-induced hyperkinesia, despite optimized medical management. The left adrenal gland was removed, and the medulla was dissected into 1- to 2-mm3 pieces in a solution containing nerve growth factor purified from mouse submandibular gland. Pieces were implanted in six tracts 3 to 4 mm from a previously placed cannula in the left putamen. Through the cannula, nerve growth factor was infused for 23 days for a total dose of 3.3 mg. Clinical assessment consisted of global ratings for rigidity and/or hypokinesia and for drug-induced hyperkinesia. Measures of gait and fine-motor control were also made. The motor readiness potential and auditory evoked potentials were recorded. The patient underwent follow-up closely for 4 months before and 13 months after grafting. She experienced no ill effects from any of the procedures, and antibodies to murine nerve growth factor, which closely resembles human nerve growth factor in amino acid sequence, did not develop. In the first postoperative month, she had a marked decrease in rigidity on the right side and a decrease in hyperkinesia. As with other patients with adrenal grafts but without nerve growth factor support, this improvement diminished during the second month. However, unlike these previous patients, our patient continued a slower phase of improvement that appears to have extended for at least the next 11 months. This course of improvement can be seen in the scores from global ratings of hypokinesia and/or rigidity, as well as amplitude of the motor-readiness potential. In addition, there was a tendency toward a decrease in the number of steps she needed to reverse direction while walking. There was no change in scores for hyperkinesia, speed of walking, or tests of fine motor control. From this single-patient study, it is not possible to draw conclusions about the mechanism of therapeutic effect or the eventual clinical utility of this approach. It seems, however, that nerve growth factor treatment may be safe in human beings and that it may prolong the effect of adrenal chromaffin grafts, consistent with earlier basic science findings.