TOXIN PRODUCTION OF THE MENINGOCOCCUS 541 



the pia mater was turbid along the vessels, with here and there small collections of pus. 

 Meningococci were found in the pus and in the blood. 



Flexner (19076) made a number of experiments on monkeys, mostly Macacus rhesus. 

 After intraspinal injection of i to 1 agar slope he found that the monkeys became generally 

 weak and apathetic ; the head drooped so as to touch the floor of the cage ; occasionally, 

 however, it was retracted ; death occurred in 18 hours to 4 days as a rule, and was not 

 infrequently preceded by general convulsions. Post mortem, the chief lesions were lepto- 

 meningitis, particularly at the base of the brain, encephalitis and abscesses, haemorrhages 

 into the pia, inflammation of the dorsal root gangUa, and acute endarteritis of the vessels. 

 The inflammation of the meninges extended into the membranes covering the olfactory 

 lobes and along the dura mater into the ethmoid plate and nasal mucosa, which was often 

 inflamed and beset with haemorrhages. Diplococci were found in the meningeal exudate 

 and in the nasal mucosa, but were not cultivated from the latter situation. They were 

 also present in the sero-purulent fluid in the ventricles. 



By giving small repeated doses Flexner succeeded in setting up a chronic meningitis 

 lasting for several weeks. Post mortem, there was abundant exudate, rich in meningococci ; 

 the foramen of Magendie was closed, and hydrocephalus and pyocephalus with ependymitis 

 and dilatation of the ventricles were found. Neither in acute nor chronic cases did the 

 internal organs, apart from the central nervous system, show any marked changes. Occa- 

 sionally the organism is found in the blood stream. 



Flexner found that not all the monkeys developed the disease. Those that did so 

 generally died within 2 days, or else recovered after a severe illness. From his experiments 

 it is clear that the disease is more acute in monkeys than in man. 



M'Donald (1908) confirmed Flexner's results in monkeys. Though unable to infect 

 rhesus monkeys, he obtained successes with CalUthrix by sub-dural inoculation of cerebro- 

 spinal fluid from human cases of disease. 



The experimental lesions which we have discussed are not produced with the regularity 

 that one might expect, partly because the meningococci themselves vary considerably 

 in virulence, and partly because the susceptibility of different animals — even of the same 

 species — varies within a wide range. 



The variations in virulence of the meningococcus depend on the source of origin 

 of the strain, the length of time it has been isolated, the age of the subculture, the 

 nature of the medium (Murray and Ayrton 1924), and doubtless on other factors. 

 When freshly isolated, some strains are of sufficient virulence to kill mice inoculated 

 intraperitoneally in a dose of about 100,000 organisms, but others are far less 

 virulent. It has, however, been shown by Miller (1933, 1934-35) that if the 

 culture is suspended in a solution of gastric mucin, as few as 2 to 10 organisms 

 of a bighly virulent strain suffice to kill a mouse. By frequent mouse passage, 

 using organisms suspended in mucin, a given strain may be kept at its maximum 

 degree of virulence. Alternatively it should be frozen and dried. 



Toxin Production. — Flexner (1907a) pointed out that one of the earliest results 

 of intraperitoneal inoculation into guinea-pigs was a marked fall of temperature. 

 This is not the normal course in an acute infection, and he was led to conclude that 

 the animals died from the effects of a poison liberated from the bodies of the 

 organisms. Albrecht and Ghon (1901) found that filtered cultures were vrithout 

 effect on mice, but that 24-hour cultures heated to 65° C. for 1 hour, when injected 

 intraperitoneally into mice, produced death with the same picture as that found after 

 injection of living cocci. Subsequent observers have found that the dose of dead and 

 of living organisms necessary to kill mice is practically identical. Thus Neill and Taft 

 (1920) found that 4,000 million living organisms injected intraperitoneally killed 6 

 out of 10 mice, whereas the same dose of dead cocci killed 5 out of 10. M. H. Gordon 



