Prolonged Intrathecal Infusion of Thyrotropin Releasing Hormone in Amyotrophic Lateral Sclerosis a

Amyotrophic lateral sclerosis (ALS) is a disease of unknown cause resulting in progressive loss of voluntary motor function.'*2 Several etiologic theories have been proposed including viral, toxic, genetic and metabolic but none is supported by reproducible clinical or experimental data. Recent interest in the role of neuromodulators in a variety of neurologic disorders has suggested the possibility that defective neurotrophic influence might be a factor in ALS. This view is strengthened by the fact that clinical and pathological damage is essentially confined to the voluntary motor system, suggesting that an essential neurotrophic substance(s) for this system might be defective. Alternatively, one might consider that pharmacologic doses of a motor system neurotrophic agent might slow motoneuron loss even in the absence of a primary defect in its function. Recent interest has centered on two candidates with demonstrated activity as an alpha motoneuron neuromodulator. One, a 56.000 Dalton protein derived from denervated muscle and named "neuroleukin",'" and the other, thyrotropin releasing hormone (TRH), a tripeptide originally described for its hypophysiotrophic action. In 1984 Gurney et a1.5*6 reported that 1 1 of 20 patients with ALS had serum antibodies against a muscle derived alpha motoneuron trophic factor. They demonstrated that this antibody suppressed reinnervation in botulinum treated mice and suggested that the antibody was possibly involved in the pathogenesis of ALS. This work has not been confirmed by more recent studies' and Wakata et a1.* have pointed out that defective reinnervation is not a feature of ALS. Over the past several years increasingly persuasive evidence has suggested that TRH serves an important role as a neuromodulator of the voluntary motor system or a t least the alpha motoneuron. Substantial amounts of TRH are present in spinal cord9*'' particularly in the anterior horn in nerve terminals ending on alpha motone~rons"-'~ which contain TRH receptors." Physiologically, TRH enhances spinal cord mono-