Investigations on the Pathogenesis of Tetanus III

Abstract

Summary and Conclusions In this and previous communications, investigations on the pathogenesis of tetanus have been reported. The theories of Courmont and Doyon, Meyer and Ransom and Abel have been subjected to experimental tests. We believe to have established the following facts: Tetanal toxin does not reach the C-N-S directly by way of the circulation. This follows from an observation referred to as the R-(route) phenomenon. It was found that the amount of circulating antitoxin which protects animals from death is determined by the route of introduction of the toxin. The same test-dose of toxin, when injected by the intracutaneous or intramuscular routes, requires up to 80 times more antitoxin than after intravenous injection. This result is obviously incompatible with the assumption that the toxin reaches the C-N-S from the tissue after absorption into the circulation.Tetanus cannot be explained by an action of the toxin on the sensory nerve-endings (Courmont and Doyon). Section of the posterior spinal nerve-roots does not influence the R-phenomenon or local tetanus.Tetanus cannot be explained by the activity of a secondary toxic substance formed in the muscle (Courmont and Doyon) or in the C-N-S (Firor, Lamont and Shumacker). Transverse lesions of the dorsal cord, followed by intravenous injection of antitoxin and intramuscular injection of toxin into one hind leg, confines tetanus to the lower extremities and considerably prolongs the survival-time of the experimental animals. This shows that generalized tetanus cannot be explained by a vascular transport of a secondary toxic substance to higher levels of the C-N-S.Tetanal toxin reaches the C-N-S by way of the motor nerves. The R-phenomenon disappears after section of the peripheral nerves or anterior roots.Tetanal toxin spreads within the C-N-S. As mentioned under the third conclusion, after intravenous injection of antitoxin, intramuscular injection of toxin into one hind leg and transverse lesion of the cord, tetanus remains confined to the lower extremities. This shows that interruption of the neural pathways within the cord prevents the passage of the toxin to higher levels of the C-N-S. Moreover, the appearance of tetanus in both hind legs proves the migration of the toxin from one side of the cord to the other.Local tetanus is of central origin. Under optimal experimental conditions antitoxin is 80 times more potent by the intraventricular than the intravenous route in preventing local tetanus in the hind leg. Since the possibility could be excluded that the intraventricularly injected antitoxin reaches the myoneural junction by way of the nerve this experiment shows conclusively that local tetanus is due to an action of the toxin on the C-N-S.Our experiments therefore confirm the nerve-carriage theory of Meyer and Ransom in all essential points.Our results provide conclusive evidence for the existence of the blood-C-N-S barrier. Since tetanal toxin is extremely toxic when injected into the lumbar cord its inability to reach the C-N-S by way of the circulation can be explained only by an impermeability of the capillaries of the C-N-S to the toxin. This, in connection with the electro-negative charge of tetanal toxin, confirms the rule of Friedemann and Elkeles according to which the blood-C-N-S barrier is impermeable to electro-negative substances.It is now established that an inanimate substance can be transmitted within the nerve to the central nervous system. The implications of this fact for the pathogenesis of neurotropic virus diseases are discussed.