In case of cerebral disturbances without melanemia of the brain the existence of non pigmented parasites must not be forgotten. These have been repeatedly found in large numbers in the brain (Marchiafava and Celli). They may be either parasites that elaborate no pigment or young forms of pigment producing parasites.

The transitory disturbances of the brain, therefore, find their explanation in the lessened amount of blood as a result of accumulations of infected erythrocytes; the long continued functional disturbances in the capillary and larger hemorrhages and in the derangements of nutrition produced by the interruption of the circulation. Whether a toxin is also to be taken into consideration can only be conjectured, though, judging from the peripheral neuritides repeatedly observed after malaria , this is very probable.

Some of the gastro intestinal disturbances, like vomiting and profuse diarrhea, are undoubtedly best explained by the accumulation of erythrocytes in the capillaries of the gastro intestinal mucous membrane. It has been stated in a previous section that these accumulations may lead, as in the brain, to thromboses, to capillary hemorrhages, and to necroses.-

The flooding of the duodenum with bile, as is not infrequent in malaria , may likewise provoke these functional disturbances, especially the bilious vomiting.

In addition to these, there are doubtless other factors not yet fully understood. The vomiting during the chill, for instance, is probably nervous in character. To what extent toxins come into play we cannot at present say.

The sensory disturbances, like cardialgia and colique seche, are not yet susceptible to explanation.

The intermittent hemorrhages from the intestine, stomach, and the esophagus, as well as the acute ascites, have been attributed by Frerichs to occlusion of the portal capillaries by pigment.

The enlargement of the liver is due to hyperemia, swelling of the endothelial and parenchymatous cells, and the invasion of pigmented macrophages. The atrophy of the liver is, according to Frerichs, due to occlusion of the portal capillaries; according to Bignami, to a thrombosis of the portal vein. Still, the most frequent cause seems to be general marasmus.

The icterus, which may vary from very slight to most intense, is at present regarded as polycholic in character. During the infection large quantities of corpuscular debris are brought to the liver for further reduction. The product of this reduction is bile. These corpuscular fragments consist in part of infected erythrocytes, but in part, too, of necrotic erythrocytes which undergo degeneration as a result probably of the toxin.

It is likely that the hemoglobin of these fragments comes to the liver in a soluble condition, even though, so far as I know, no one has demonstrated it in the blood plasma. In three cases which I investigated I obtained a negative result; nevertheless, many circumstances go to indicate that the corpuscular debris is incapable of holding the hemoglobin. This is apparent microscopically after the excapsulation of the parasite, when we usually see a completely colorless shadow, the remains of the hemoglobin having disappeared.

Whether the melanin is further reduced by the liver cannot be stated with certainty. This is, at least, true, that a larger amount of raw material than normally is brought to the liver, and that from this polycholia results. The polycholia is frequently expressed by bilious vomiting and bilious evacuations. The icterus may be compared to that which occasionally accompanies other infectious diseases, like sepsis, pneumonia, etc., with this difference, that in malaria it has a more legitimate place.

If the destruction of blood corpuscles occurs rapidly and in great numbers, so that Ponfick's postulate in relation to the destruction of a sixth is fulfilled, in addition to icterus, hemoglobinuria is seen.

We stated before that we attribute the hemoglobinuria to a solution of the blood corpuscles within the vessels. Pellarin's view that the hemoglobinuria is produced by renal hemorrhages has been found wanting, inasmuch as there are cases in which no renal hemorrhages were found and others in which it was possible to demonstrate the hemolysis in the peripheral' blood.

Karamitsas was probably correct when he assumed that Pellarin's renal hemorrhages were infarcts the result of thromboses by shadow corpuscles. Still, the final cause of the hemolysis in blackwater fever or in postmalarial quinin intoxication is unknown. For the hypotheses in regard to it we refer to the corresponding sections.

The anuria and uremia of blackwater fever are explained by the occlusion of renal vessels by shadow corpuscles and granular detritus.

The latent fevers still show much that is problematic. The difficulty lies in the absence or insignificance of the fever. This is probably due to the small number of parasites ordinarily found in these conditions. Nevertheless, there is some question whether they may not be due to a changed reaction on the part of the organism, a certain tolerance of the vasomotor centers toward the virus. We know, for instance, that latent fevers usually occur after repeated typical attacks. It is, therefore, possible that the centers may have acquired a certain insensibility to the poison. The positive symptoms of the latent fevers are commonly such as are manifested by these persons under other circumstances. Further than this we cannot follow the pathogenesis.

In the preceding we have endeavored to show the pathogenesis of the most important symptoms. We refrain from analyzing the occasionally occurring symptoms, since it would carry us too far and we would often be forced into the realm of pure speculation. This is especially true of the complications which we have reviewed in the clinical part as far as their pathogenesis is known.