Dialysis Dementia: An Epidemic That Came and Went

Beginnings In the fall of 1972, one of our dialysis patients at Cook County Hospital in Chicago began to have episodes of bizarre behavior. During these episodes, she would stutter or become unable to speak, exhibit twitching movements, and have spells of confusion or altered consciousness, at times becoming almost comatose. At first these episodes would last several days and she would recover. She was an unhappy woman, on maintenance dialysis for several years, her husband in prison for selling illegal drugs, and she had numerous children to care for. Initially, we thought her symptoms were functional; but in time, these episodes became more prolonged, she failed to recover fully, and at last she sank into a terminal coma. Then Dr. Earl Smith, chief of the renal unit at Mount Sinai Hospital, mentioned that a patient in his dialysis unit had similar symptoms. In October, while attending the Seattle meeting of the American Society of Artificial Internal Organs, he heard Dr. Allen Alfrey from Denver, Colorado, report on a series of patients whose features seemed to be similar to our two puzzling cases. He referred to this clinical entity as “a syndrome of dyspraxia and multifocal seizures associated with chronic hemodialysis.”1 It clearly was something that had not been seen before. Dialysis Dementia Impressed with the profound mental deterioration in our patients, we decided to publish our two cases under a title emphasizing this particular aspect. We considered Dialysis Madness, an analogy of Myxedema Madness and Megaloblastic Madness, but settled on Dialysis Dementia 2 as more catchy and euphonious. Over the years, this became the most widely used name, even though Dr. Alfrey’s designation was more scientifically accurate. In 1974, the Lancet published our somewhat dramatic description of “a fatal and mysterious illness” consisting of “progressive dementia, dyspraxia, bizarre involuntary movements, facial grimacing, myoclonus, and characteristic electroencephalographic changes.”2 Prealuminum Days It was mysterious and frightening indeed. 2–5 Patients coming to dialysis would look at each other in fear and wonder whose turn would come next. Consumer groups came to the hospital wondering what was going on. At first, we had no idea what was happening. We added rubidium to the dialysate; others tried BAL, cobalt, or vitamins. Drugs were suspected when one of our patients given pentazocine (“Talwin”) for headache lapsed into a coma, with characteristic myoclonic jerks and electroencephalographic changes. Later, we learned that certain drugs could indeed cause a syndrome indistinguishable from dialysis dementia. 6 Other investigators suspected trace elements such as copper, zinc, lead, or cadmium; hypophosphatemia; a deficiency syndrome, perhaps of dopamine, 7 pyridoxine, 8 or asparagine 9; a slow virus, or possibly hypoglycemia. 10 Meanwhile, my associate Dr. Sakharam Mahurkar carried out radio-iodinated serum albumin cysternography in six patients with dialysis dementia and found abnormal ventricular reflux, stasis, and prolonged retention of the injected medium, suggesting an alteration of cerebrospinal fluid dynamics, somewhat resembling normal pressure hydrocephalus. 11 These changes, which even with the present day understanding of the role of aluminum may serve to explain the actual mechanism by which neurologic disturbance occurs, 12 were of great therapeutic interest at the time. Dr. Smith arranged for one of our patients to undergo a shunting procedure, and this seemed at first to be successful. The patient, who had been incapacitated for weeks, walked to the phone to call his wife. 3,4 Swiss investigators reported similar successes, 13 but all were transient. Other investigators reported good results from corticosteroids. An Aluminum Encephalopathy It was only fitting that the group that first described this disorder should also be the one to elucidate its immediate cause, aluminum intoxication; and in 1976, Alfrey et al. reported elevated aluminum levels in the brain gray matter, bone, and other tissues of patients with dialysis dementia. 14,15 Other reports confirming the association with aluminum followed, from the North of England, 16 the Mayo Clinic, Michigan, Canada, France, and then from many other parts of the world. In Einthoven, Dr. Flendrig reported an outbreak of encephalopathy following the erosion of an aluminum electrode into the dialysate. 17 In our unit at Cook County Hospital, we had resisted the installation of deionizers, following the precepts of my former chief, Dr. Willem Kolff, who had always believed that if dialysis were to become widely available it should be simple and inexpensive. However, when we contacted the Chicago Water Board we discovered that, in 1972, they had changed the method of purifying water from lake Michigan from half ferrous sulfate and half aluminum sulfate to the exclusive use of aluminum salts. We were able to correlate water aluminum levels with new waves of dementia in our unit 18 and, needless to say, installed deionizers. In April of 1978, we organized an international meeting on aluminum and dialysis dementia, held in the splendid old Board of Trade Room at the Chicago Art Institute. Investigators from many parts of the world attended, including Drs. Allen Alfrey, Alkis Pierides, J.A. Flendrig, Michael Ward, Gilbert Mayor, Friedrich Port, and Marshall Schreeder. As the issue of possible detrimental effects of aluminum containing binders arose, Dr. Geoffrey Berlyne reminded the audience that long ago he had warned against the dangers of aluminum intoxication. 19 Aluminum in the Gut For a while, we became a virtual information center on dialysis dementia, as many physicians called asking for information and help with similar cases. It seemed strange indeed that sporadic cases continued to occur despite the use of deionizers for water purification. In Oak Park, Illinois, Dr. Robert Muehrcke saw a patient who had the same syndrome, despite adequate use of deionizers in a unit of some 80 patients, none of whom were affected. As time went on, measurements of aluminum levels became available, then routinely used. It soon became apparent that aluminum accumulation could cause microcytic anemia 20,21 and bone disease 22 and that aluminum hydroxide was not entirely non absorbable, but that small amounts could be absorbed into the blood stream. Nevertheless, with routine monitoring of blood aluminum levels, outbreaks of neurologic disease became, for practical purposes, extinct except for rare instances, such as when aluminum electric pumps 23 or malfunctioning reverse osmosis systems 21 contaminated the dialysate. Acute Encephalopathy In 1986, however, when aluminum compounds were still being used, my associate Dr. Asad Bakir saw a patient with rapid onset of myoclonic jerks, stuttering or mutism, refractory seizures, coma, and death. Three other patients developed the same clinical picture in rapid succession. All had myoclonus reminiscent of dialysis dementia and exceedingly high aluminum levels, up to 1,140 μg/dl. Dr. Bakir found that all had in common the ingestion of Shohl’s Solution (sodium citrate) and aluminum hydroxide. These had been prescribed to prevent hyperphosphatemia and acidosis in patients made compliant by a recently hired conscientious nurse who had undertaken intensive patient education. Dr. Bakir hypothesized that citrate must have facilitated the intestinal absorption of aluminum. Our experience was presented at the annual meeting of the American Society of Artificial Internal Organs and published in the Transactions. 24 Dr. Bakir undertook a case control study and found that patients on aluminum hydroxide and sodium citrate had much higher serum aluminum levels than those taking aluminum hydroxide alone; also that healthy volunteers taking aluminum hydroxide excreted more aluminum in the urine when citrate was added. 25–27The New England Journal of Medicine was very interested in the paper, but would not publish it on the grounds that it constituted duplicate publication. Dr. Jack Coburn, however, acknowledged the importance of this observation in an editorial in that journal. 28 Later Dr. Alfrey’s group showed that citrate enhanced the absorption of aluminum by opening the tight junctions of the intestinal mucosa. 29 Once people learned not to use citrate with aluminum hydroxide, no more such acute encephalopathic cases were observed. Eventually, the realization that aluminum accumulated in bone led to its abandonment as a phosphate binder and its replacement by calcium carbonate, itself not an ideal compound because dialysis patients are prone to metastatic calcification. Decline Despite the abandonment of aluminum hydroxide as a phosphate binder in dialysis patients, the danger of aluminum toxicity remains real. Aluminum toxicity has been reported in infants receiving intravenous therapy 30 or aluminum containing infant formulas, 31 in aluminum smelter workers, 32 in patients treated by plasma exchange 33 or with sucralfate, 34 and possibly in some people using aluminum pots and pans in cooking. 35 The epidemic form of dialysis dementia, however, has disappeared, just as years ago Pink Disease vanished when mothers stopped using mercury teething powders for their babies.

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