Large motor neuron involvement in Stiff-man syndrome: a qualitative and quantitative study.
Stiff-man syndrome (SMS) is characterized by fluctuating muscular rigidity and spasm. Recently, antibodies against glutamic acid decarboxylase (GAD), the enzyme catalyzing the synthesis of y-amino butyric acid (GABA), have been detected in SMS patients. An autoimmune mechanism against GAD was thus proposed for the suppression of GABAergic inhibitory interneurons, resulting in rigidity and spasm. We conducted quantitative investigations on the ventral horn of the spinal cord and its GAD immunoreactivity, post mortem, in a SMS patient and four controls. In the spinal cord of the SMS patient, we found a 70%, 33% and 27% reduction (P < 0.05) in the density of neurons with somal areas of 1000-1500 microm2, 500-1000 microm2, and 0-500 microm2, respectively. The density of neurons with a somal area greater than 1500 microm2 was not reduced, although some neurons in this class showed central chromatolytic changes. The affected muscles exhibited neurogenic atrophy. GAD-like immunoreactivity in the spinal gray matter was not significantly decreased. The density of Purkinje cells, known to contain high amounts of GAD, was not significantly reduced. While the co-occurrence of elevation of anti-GAD antibody in the serum and reduction in the density of small spinal neurons was confirmed, that of smaller alpha-motor neurons and gamma-motor neurons, the qualitative changes in larger alpha-motor neurons, and the preservation of spinal GAD-like immunoreactivity and non-spinal GAD-containing neurons suggest the involvement of factors other than autoimmune mechanisms through anti-GAD antibodies. More diverse mechanisms may be associated in the pathogenesis of SMS.