FIRST ANNUAL HEALTH SCIENCE CENTER RESEARCH WEEK
October 16-20, 1995

B.J.Wilder, M.D., Russell W. Hurd, M.S., Scott C. Franzcek, M.D.
Wendell R. Helveston, M.D., Basim M. Uthman, M.D.
Department of Neurology and Brain Institute, University of Florida,
Gainesville, FL 32610

INTRODUCTION

Free radical mediated mechanisms have been suggested as contributing to the development of several neurodegenerative diseases. Several excellent reviews have recently addressed this subject.

In patients with a hereditary seizure disorder, Progressive Myoclonus Epilepsy of the Unverricht Lundborg Type (PME-UL), characterized by myoclonus, generalized and absence seizures and deterioration in mental function, we found increased activity of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD, SOD3). An increase in EC-SOD could potentially disrupt a balance in oxidative metabolism since enhanced H2O2 production without compensatory changes in catalase or glutathione peroxidase (GSHpx) may lead to increased production of more potent free radicals such as the hydroxyl radical. This was recently confirmed in animal studies by Oury et al. in which mice, transgenic for the human EC-SOD gene, had markedly increased susceptibility to oxygen-induced seizures.

Patients were therefore placed on antioxidant vitamins and minerals (vitamin E, riboflavin, selenium and zinc). Over a six month period, parents and nursing home staff indicated there was some improvement in patient condition, particularly in alertness. N-Acetylcysteine (NAC), a sulfhydryl amino acid has several characteristics promoting its usage as an antioxidant, including scavenging of the hydroxyl radical, increased synthesis of reduced glutathione and diminished production of H2O2. NAC administration was initiated and, at a dosage of 4-6 grams daily, produced a reduction in myoclonus, increased mobility, and improvements in speech, alertness, and self-care.

Objective improvement in patients with PME-UL with NAC suggested its usage in other neurodegenerative disorders. Our initial emphasis was the treatment of hereditary movement disorders, particularly the hereditary ataxias. More recently, patients with other neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and Alzheimer's disease have been treated with NAC. We report here results of studies with NAC conducted over the last 30 months.

PATIENTS AND METHODS

A total of 61 patients have been treated with NAC for periods from 1 month to 30 months. Forty eight (48) patients continue in these studies. Patients receive NAC either in liquid (Mucomyst or Mucosil), as a powder (Spectrum Chemical, Gardena, CA, USP grade), or as a flavored suspension (West Labs Pharmacy, Gainesville, FL) dissolved in juice or cola. In this open label study, dosage is 4-6 grams/day for adults and 60 mg/kg/day for children divided into 2-3 doses.

Because of reports of magnesium (Mg) deficiency subsequent to treatment with NAC9, all patients receive supplemental Mg. In this report, we include patients with PME-UL (N=4), hereditary ataxias (N=32), multiple sclerosis (N=10), amyotrophic lateral sclerosis (N=3) and Huntington's Chorea (N=2). At baseline, all patients received a videotaped neurological exam, and the initial 40 patients received a FRESA analysis (FRESA Labs, Redmond, WA) which included red blood cell (RBC) activity levels of GSHpx, glutathione reductase, glutathione transferase, catalase, superoxide dismutase (SOD1) and plasma selenium, zinc, manganese and copper. Disease specific neurophysiological, neuropsychological, ophthalmological and genetics testing was also performed.

C. FRIEDREICH's ATAXIA (FA) (N=7)

A 21 year old female with FA was referred for treatment with NAC. FRESA analysis indicated low selenium and GSHpx activity along with other enzyme abnormalities. Similar antioxidant changes were found in 3 additional patients with FA (Helveston et al. in press). After 8 months treatment with NAC and other antioxidants, this patient's FRESA profile was normal. During this time, there was an improvement in proprioception and a slight decrease in ataxia.

Greater than 90% of FA patients develop a cardiomyopathy, which is a major cause of early death. Until recent years, cardiomyopathy was a major cause of childhood death in low selenium areas of China (Keshan Disease) until a program of selenium supplementation of table salt was initiated in affected areas and population glutathione peroxidase levels increased.

(results of other neurological disorders participating in this study have been omitted)