The German pathologist Friedrich Theodor von Frerichs published a monograph in 1851 which focused more on the Uramische Intoxikation and its clinical signs and more than what happened to the kidney. His treatise is a medical classic, although the chemical data on which it was based were shaky: the rise of blood concentration of urea was unpredictable, and he mistakenly considered that ammonium carbonate, which he also found in the blood, was responsible for the toxic effects of uremia.

A century later, Baker and Knutsen divided the symptoms of uremia roughly into two groups: “those of depression of the central nervous system, such as apathy, muscular weakness, stupor and coma; and those of neuromuscular hyperexcitability, namely, increased tendon jerks, muscular twitchings, and convulsions.” They noted the patient was fatigued and unable to concentrate, and with progression of the disease the patient was more apathetic, with sleep being interrupted by restlessness and insomnia. Speech became unintelligible. Symptoms of neuromuscular hyperexcitability, such as “fibrillary muscular twitchings,” were present. The convulsions usually appeared late and were generalized. Focal or Jacksonian seizures could occur (and still be present after correction of uremia), and occasionally these epileptiform seizures continued even after the patient had recovered from the uremia.

Monoplegias, hemiplegias, aphasias, and apraxias were all observed. Baker and Knutsen [8] wrote, “Of the motor symptoms, hemiplegia is the most frequent. This usually is of a flaccid type and is often ascending, producing Landry’s type of paralysis. The involvement is transient, lasting hours or days and then disappearing, only to return after a variable period. Two of our patients had such episodes; in one the involvement implicated all limbs, resulting in quadriplegia.”

Previous pathology studies on brains in patients with uremia showed demyelination and included large areas of the white matter, but there were widely divergent lesions and other factors (ischemic insults) may have played a role. In the acute illness, the predominant alteration occurred within the cortical neurons, which revealed an acute change in the nerve cells. In the more chronic illness, the most striking changes were parenchymal rather than neuronal and consist of focal and perivascular areas of demyelination and necrosis.

The key article (Fig. 2) for medical historians to consider was “a pathoanatomical study of brains of 104 patients dying in renal insufficiency with reference to the influence of complicating factors” published in 1961 [9]. The Danish pathologist Steen Olson found in nearly all the brains a well-characterized neuronal degeneration. Some localizations were more frequent and most severely affected, and these were, in no particular order, the sensory nuclei of the brain stem, the reticular formation, and the cerebral cortex. However, the Purkinje cells, the nucleus caudatus, claustrum, the thalamus, the globus pallidus, the putamen, the hypothalamus, the hippocampus, and somatic efferent nuclei were morphologically unaffected. They concluded:

Summarily, it may be said about the pathoanatomic changes in the brain in so polymorphous a material as the one described that the eliciting factors and the complicating conditions highly influence the picture. In the frequent cases of acute ischemic anuria we must especially reckon with the interference of circulatory failure, which not only causes injury to the renal parenchyma, but also, which is just as important for the patient, often gives rise to brain lesions [9] (emphasis added).