J Clin Pathol 1981 ;34:1285-1294

Dialysis encephalopathy, bone disease and anaemia:the aluminium intoxication syndrome duringregular haemodialysisIS PARKINSON, MK WARD, DNS KERR

From the Department of Medicine, University of Newcastle upon Tyne

DIALYSIS ENCEPHALOPATHY

Clinical featuresDialysis encephalopathy, now attributed to alumin-ium intoxication, is a complication of prolongedhaemodialysis first described in 1972.1 Initially thecondition was over-diagnosed, and at meetings of theEuropean Dialysis and Transplant Association andthe American Society of Nephrology almost half theaudience claimed to have seen at least one case. Inthe light of subsequent studies it seems likely thatmany of these claims were based upon the mis-interpretation of other neurological syndromes inrenal failure.However to one who has lived through an

"epidemic" of this disease, the clinical picture isreadily distinguished from that of most other neuro-logical disorders. Usually the first symptom is acharacteristic alteration in speech; this is partly adysarthria due to disordered muscle action and, at theheight of an attack, the tongue can be miraculouslyloosed by an injection of diazepam.2 However as thedisease progresses dysphasia coexists with dysarthria.Speech disturbance is initially intermittent, oftenprecipitated by dialysis, but becomes continuous.Other early features are myoclonic jerks and grandmal seizures. Two characteristic features are dys-praxia, which affects the handwriting at an earlystage, and rapid fatiguability which causes perform-ance of all structural tasks to deteriorate within afew minutes of sustained effort. Global dementiasupervenes but insight is often retained until late inthe illness; this is a distressing feature since thepatient has often seen his fellow patients die of thesame condition and appears to know what ishappening to him. In the terminal stages facialgrimacing, myotonic spasms and dysphagia interferewith eating and lead to inhalation pneumonia. Deathoccurs from inanition, infection or deliberatewithdrawal of treatment.

Some of the data quoted are taken from a PhD thesis by ISP.

The major symptoms of 21 patients seen inNewcastle are shown in Table 1. Fuller descriptionsof the symptomatology are contained in severalrecent reviews.3-7

Table 1 Dialysis encephalopathy syndrome in 21 cases

Dysarthria/dysphasia 21Dementia 21Myoclonus 16Seizures 8Ataxia 8

Lumbar puncture has been uninformative; nearlyall authors have reported normal CSF pressure, cellcount and concentrations of protein, glucose andchloride. The brain atrophy to be expected in adementing disease has been inconspicuous in the fewreported studies; air encephalograms were normalin two patients8 9 and so were computerised axialtomographic (CAT) scans in 14 others.'0 11 Howeverthe Chicago group found slight dilatation of theventricles on CAT scanning in one patient andabnormal CSF dynamics, revealed by cysterno-graphy with radioiodinated human serum albumin,in seven others.'2 Isotopic brain scans have beenconsistently normal.8-'2The one laboratory test that has proved extremely

useful is the electroencephalogram (EEG). A charac-teristic pattern of spikes and slow waves appearsearly in the course of the disease.'-313

After successful renal transplantation patientswith early disease gradually recover (Table 2).1415Over the course of one or two years speech deficitdiminishes but seldom disappears completely.Patients who have regained normal speech under thequiet conditions of home life become dysphasic againwhen embarrassed-for example, by being shown infront of a large medical audience. When patients aretransplanted late in the course of the disease thedownhill progress is not arrested. It is thereforecrucially important to diagnose the disease at anearly, reversible stage. This is difficult even when

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Table 2 Result ofattempts to reverse encephalopathyat Newcastle

Cadaver transplantationGraft successful:

Early neurological disease stabilisedEarly disease progressedLate disease progressed

Graft failed; patient returned to dialysis with high aluminiumdialysate: dementia progressed

Transferred to purer dialysateMoved to Sunderland*: disease stabilisedDialysate made from distilled or deionised water: disease

stabilised

Total

5

2

3

*Aluminium concentration in Sunderland tap water < 30 gg/I.

suspicions are heightened by a continuing epidemic.The early features probably include a reduced

performance IQ and abnormal responses to othertests of higher functions such as calculating ability.Two studies have shown progressive impairment ofsuch tests with length of exposure to dialysis; onewas in Newcastle, at a time when aluminium exposurewas unchecked and cases of encephalopathy werestill appearing;16 the other was in a centre wherealuminium exposure was apparently suspected sinceplasma aluminium was included in the investiga-tions, but no results for serum aluminium werereported and no information was given on the localincidence of encephalopathy.17 A speech-screeningassessment, carried out by a speech therapist, hassuccessfully detected patients with high aluminiumexposure and predicted progression to overt encepha-lopathy.18 However early diagnosis usually dependson the alertness of the clinician to subtle changes inpatient behaviour and free use of the EEG insuspected cases.

PathologyCompared with the devastating clinical features, thepathological findings have been slight and havevaried in different accounts. The topic was recentlyreviewed by Cartier.19 Cerebral atrophy has beenslight or absent. Non-specific gliosis, accumulationof lipofuchsin or focal oedema have been describedin most series1 8-1120 but in some the majority ofpatients have been described as microscopicallynormal."112 Prominent corpora amylacea weredescribed in a few patients2 20 along with a few otherminor and inconsistent abnormalities. The lacunaedescribed in three patients in one study9 may wellhave been the result of hypertension.Another inconstant feature reported from Denver,

seen in only two patients, was loss of Purkinje cellsfrom the cerebellum.20 This, however, was a more

constant and impressive feature in Newcastlepatients ;21 some had virtually complete loss ofPurkinje cells. Two brains studied at Rennes by a

combination of electron microprobe analysis andelectron microscopy revealed numerous lysosomes inbrain neurones; these contained very numerous finemicrocrystals identified as aluminium phosphate.22

Surprisingly little space has been devoted toneuropathology in the publications on dialysisencephalopathy. It seems unlikely that the last wordhas been spoken on this topic.

Role of aluminiumInitially the cause was sought in the known featuresof chronic renal failure, but with negative results.Half-way through the Newcastle epidemic 14encephalopathic patients were compared with 32other patients on regular haemodialysis. There wasno significant difference in the control of uraemia, asjudged by predialysis plasma creatinine (encephalo-pathy 1190, range 670-1272 v control 1102, range781-1418 ,umol/l) or mean blood pressure (130/76 v139/84 respectively). Histopathological studiesshowed no evidence of other neurological diseaseand the younger encephalopathic patients were oftenremarkably free from cerebral atheroma at necropsy.Culture of the brains for slow viruses yielded negativeresults with one exception. For a brief period phos-phate depletion was considered to be a possiblecausative or aggravating factor since phosphaterepletion produced a temporary improvement.23 How-ever the patients soon resumed their inexorable down-hill course despite continued phosphate treatment.Alan Alfrey, who first described the disease, was

convinced from the start that it was an intoxication.He embarked on a long search for trace-elementaccumulation in dialysis patients at Denver andturned up a few false clues such as modest accumula-tion of tin or deficiency of rubidium.24 In 1976 hereported a much more striking abnormality-asubstantially increased concentration of aluminiumin several tissues of patients dying of encephalo-pathy;25 the concentration in brain grey matter wasten times as high as in control uraemic subjects, andin muscle and bone it was up to 100 times as high.The results were soon confirmed in Eindhoven26 and,for the brain, in Newcastle (Table 3).27

In Europe the evidence that aluminium was the

Table 3 Brain aluminium concentrations in Newcastlepatients27

Cause of death No of Aluminium concentrationspatients (tug/g dry weight)

Grey matter White matter

Encephalopathy 7 20-4 (31) 6-9 (21)Other complications of

regular haemodialysis 12 5-1 (62) 3-5 (50)Uraemia (not dialysed) 2 2-9 (11) 2-7 (7)

Figures in parentheses indicate the number of tissue samples analysed.

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Dialysis encephalopathy, bone disease and anaemia: the aluminium intoxication syndrome

cause of dialysis encephalopathy was accepted almostat once. This rapid conversion of nephrologists oweda great deal to the dramatic account by Flendrig andhis colleagues26 of the outbreak at Eindhoven. Twodialysis centres in the same city shared a commonwater supply, low in aluminium, but one of thesecentres was the seat of an outbreak of fatal encepha-lopathy which affected six patients. The source of thealuminium was traced to two aluminium anodeswhich were part of a cathodic protection systemagainst corrosion in the boilers. When these anodeshad been removed and the unit had moved to a newhospital a few months later, the outbreak ceased. Inthe United States there has been greater reluctance toaccept the evidence, partly because of the authorita-tive opposition of Dr Allen Arieff.28 The alternativetheories of causation have been fully reviewed byBone10 but in the authors' view they are of historicinterest only. However, for the sake of Americansceptics the evidence for and against aluminium asthe cause will be summarised.The evidence for tissue accumulation ofaluminium

has been set out above. However, two other investi-gations have not confirmed it. Platts and Hislop29found only a modest increase and Pascoe andGregory30 found none, but these were small studiesand the latter has only appeared in abstract. Arieff28found brain aluminium concentrations in dementedpatients fifteen times higher than normal but rejectedthis as evidence of cause and effect since he also foundhigh concentrations of aluminium in the brains ofpatients dying of hepatic coma, metastatic cancerand uraemia without encephalopathy. Berkseth andShapiro31 found high aluminium concentrations(20-0, 17-6, 17-6, 15-6 mg/kg) in the brains of fourpatients who died after 32-36 months' exposure tohigh-aluminium dialysate, only onc of whom hadencephalopathy, and lower concentrations (8-6, 8 6)in two patients who died after nine months treatmenton pure dialysate following four and 36 monthsrespectively on high-aluminium dialysate, of whomone was encephalopathic. They did not feel that thisevidence supported aluminium deposition in thebrain as the pathogenesis of the brain lesion, thoughthey adduced considerable epidemiological evidencefor aluminium as the cause of the disease.However, in support of Alfrey's hypothesis, a

study from Rennes showed substantially higher greymatter aluminium in dialysed patients with encepha-lopathy than in those without encephalopathy,32 andfurther work at Denver substantiated the earlyresults, showing almost no overlap between theencephalopathic and unaffected dialysis patients.33Although the conflict of evidence is disturbing, itmust be stressed that measuring brain aluminium isdifficult; the most stringent precautions are necessary

to exclude contamination and no publication isinterpretable without full technical details. Weremain prepared to pin our faith on the carefulstudies at Denver, Eindhoven and Rennes along withour own from Newcastle. Fortunately for ourpatients, if not for our scientific curiosity, theopportunity for repeating these studies is vanishingand the issue may remain unresolved.

Consequently the evidence that is likely to con-vince the sceptical in the long run is epidemiological.Many outbreaks have been described in associationwith the use of dialysis fluid with a high concen-tration of aluminium, usually greater than 200tzg/l1013 26 27 32-42 An epidemiological study of thedialysis centres in the United Kingdom showed thatencephalopathy was almost unknown in those withan aluminium concentration of less than 50 ,tg/lin water used to make dialysis fluid, while its inci-dence rose progressively with higher water concentra-tions (Fig. 1).43 A similar study in France led to the

1 -401

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0-c

*O 10I.-

Ca,

to

0

0

0

*3

*4

*5

06

*8 *7

1s9w 1° .1

12 18.1920

100Mean water aluminium

0 4(pUmol /l1)

200 400level (,ug /1)

,-q{E8 <8

Rank correlation= 0 69 with 20 degrees of freedomp = 0.0004Fishers Exact Test: cut off pointsAl > 50,ug/l encephalopathy> 5o/oAl 50jug/l encephalopothy< 50/0p= 0.0004

Fig. 1 Correlation of encephalopathy with meanaluminium content of the water used to make dialysisfluid in British dialysis centres. The numbers refer to theidentity of the centres.43 Reproduced by permission of theEditor of The Lancet.

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same conclusions (Cartier F, personal communica-tion, 1981).A European survey conducted by the Registration

Committee of the European Dialysis and TransplantAssociation showed that cases of dialysis encepha-lopathy were clustered in certain areas-the Northand West of Britain, Brittany, North Spain, Greeceand Scandinavia-- and that 92% of these patientshad been treated with dialysis fluid made fromunprocessed or softened water.44 In many of theoutbreaks referred to earlier in this paragraph, theintroduction of a deioniser or a reverse osmosissystem abruptly ended the "epidemic." In Newcastlecases of overt encephalopathy stopped occurringjust before the changeover to a purified water supply.This was due to the suspension of home dialysis inCumbria, the worst affected area of the region, be-cause patients were dying at such an alarming rate;although the Newcastle water supply gave rise to afew cases of encephalopathy, the incubation periodwas long and the incidence low.The protective effect of good water treatment has

been maintained as reported from Plymouth42 andSheffield45 and from several other centres (AMPierides, personal communication 1981). InNewcastle only one new case of encephalopathy hasappeared since the introduction of purified water; thispatient's home water treatment system was not re-moving aluminium adequately. One other patient,heavily exposed to aluminium before reverse osmosiswas installed, suffered some progression of his ence-phalopathy afterwards, in keeping with experienceafter transplantation in such patienits. The all butuniversal success of precautions against aluminiumexposure in eliminating this disease is the strongestargument supporting aluminium overload as the solecause. However it has to be acknowledged that watertreatment removes many other potentially toxicsubstances. Of these, only manganese has some smallclaim to an epidemiological association with thedisease34 and has been found in excess in the brains ofaffected patients,32 though in the white matter ratherthan in the histologically involved grey matter.Some supporting evidence for the role of alumin-

ium comes from the association between encepha-lopathy and high concentrations of aluminium intissues other than brain, notably bone (discussedbelow) and serum or plasma (Fig. 2). The consider-able overlap in most studies between the plasmaaluminium concentrations of patients with encepha-lopathy, and those treated at the same centre whohave not yet developed the disease,4046-48 is notsurprising; plasma aluminium, which reflects recentexposure to a source of aluminium overload, usuallythe dialysate (Fig. 3), takes a few weeks to changewhen water purification is introduced.4' Cerebro-

500-

400

300 -

0)

,,, 200-

100

0

A -No Newcastle bone disease* or encephalopathy

B - Newcastle bone disecseC - Dialysis encephalopothy

S

S

S

* S* 5

* S

I ,S,\ i\X a\ ..-

0'

Normalrange

A B C

Fig. 2 Serum aluminium (Al) in haemodialysis patients,showing high aluminium levels in bone disease andencephalopathy (for methods see reference 33).

12 -

9-

0

E

6-

E

3

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300-

A -Patients dialysed with softened waterB - Patients dialysed with deionised waterC- Patients dialysed with reverse

osmosis treated water

200-

i00-

0

b.

* 1

A B C

Fig. 3 Serum aluminium (Al) in patients on regularhaemodialysis on different forms of water treatment.Measurements were made immediately before dialysis.

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Dialysis encephalopathy, bone disease and anaemia: the aluminium intoxicationi syndrome

tap--softened

deionisedreverse osmosis-spirally wound

300

200J- -I1- 1980

Fig. 4 Effects of softening, deionisation and reverse osmosis on aluminium (Al) content of Newcastle tap water.

spinal fluid aluminium has received little attention but0

appears to have a closer association than plasmao

aluminium with the presence of encephalopathy.48 \wyThe total body burden of aluminium cannotbeV/measured easily, but can be estimated from whole 80 - \vbody neutron activation; it is raised by several grams /in patients withencephalopathy.49\

Dialysate aluminium 60 - \With one exception, all published outbreaks of <\encephalopathy have been traced to aluminium ' ocontamination of the dialysis fluid. The unusual on almn mearsource of aluminium at Eindhoven has beendescribed above; the commoner source is treatmentof surface water by the water authority to removeorganic materials affecting its colour and taste. The 20-first stage of this process is flocculation. Aluminiumsulphate is a popular flocculating agent since theresidue of alum which remains after the process doesnot affect either ortdlysihe taste of water. This ° . me.residual aluminium content varies from day to day 5 6 7 8

(Fig. 4) reflecting weather conditions which affect pHthe organic content of the water. The chemical Fig.o Effect ofpH on the proportion of ionised a,formulation of residual aluminium also varies; it um (Al) in Newcastle tap water (4 samples).changes from aluminium salts through colloidalparticles to aluminates as the pH rises. The solubilitycurve is therefore U-shaped (Fig. 5). Although the

n±l SD

lumini-

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resins of water softeners have a high affinity foraluminium they do not remove it reliably from watersupplies (Fig. 4).21 34 36 42 48 50-52 Deionisers aremuch more effective and have often been sufficientto halt an outbreak. In Sheffield they have evenpermitted improvement of affected patients.34 35However they are not totally reliable in all watersupplies (Fig. 4). Twin bed deionisers seem likely tobe more effective than mixed bed d.ionisers.Reverse osmosis has been consistently effective inNewcastle (Fig. 4) but there have been occasionalexceptions elsewhere.53 The best arrangement is awater softener, reverse osmosis and deioniser inseries; the cost is fully justified in areas with high tapwater aluminium.4' Whatever system is chosen, itshould be tested on the local water supply andmonitored regularly.When dialysate pH is carefully controlled at close

to 7-0 much of the aluminium is in colloidal form,and at this pH, dialyser clearance was found to below,54 at least in vitro. The importance of dialysisfluid pH is emphasised by the Redy system ofdialysate regeneration* which releases more alumin-ium from the cartridge when used with bicarbonate-containing dialysis fluid than with the usual acetatesolution.55 However, most studies of dialyser alumin-*See page 1283 (Rosemarie Baillod)

200-

150 {

27100

50-I

01Before After

ium clearance in vivo have showni results similar tothose in Fig. 6, which imply that much of the dialysisfluid aluminium is in solution. There is rapid uptakeof aluminium by the blood unless the dialysateconcentration is kept down to about 10 p.g/1.52 56-58In Newcastle, the use of water purified by reverseosmosis enabled zero aluminium balance across thedialyser to be achieved, but not its removal from theblood; the slight rise during dialysis shown in Fig.7c is accounted for by haemoconcentration, sinceserum aluminium is about 80°o protein bound.5'However, Graf and his colleagues, using very purewater and treating patients with higher initial serumaluminium concentrations than in the Newcastlepatients have achieved some aluminium removalfrom the body by dialysis.59 fio

Oral aluminiumStudies in the early 1970's reported hyperaluminae-mia from ingestion of aluminium-phase resins,6l andpositive aluminium balance from ingestion ofaluminium hydroxide;62 however the methods usedfor measuring aluminium grossly exaggerated theamount of aluminium absorbed and would not nowbe acceptable. Nevertheless the results have provedqualitatively correct. Alfrey's group assumed thatingested aluminium was the major source of the

iIBefore After

±

Fig. 6 Change ilserum alunminium (Al)luring a singlehaemodialysis inNewcastle patientswhose dialysis fluidwas made from waterthat was (a) untreated,(b) deionised, (c)treated by reverseosmosis.

Before After

Deionised Reverse osmosis

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Dialysis encephalopathy, bone disease and anaemia: the aluminium intoxication syndrome

overload in dialysis encephalopathy25 and soonshowed by sensitive techniques that even normalsubjects had a rise of serum aluminium within a fewdays while ingesting aluminium hydroxide.63 Thishas been confirmed for patients in chronic renalfailure who were not on dialysis64-66 or were dialysedagainst very low concentrations of aluminium.67 Ingeneral the serum concentrations attained in thesestudies have been well below those found in patientswith encephalopathy (Fig. 7). A survey conducted by

>801

80 -

- 60-

:;F

E

I) 40

20 -

0

i

A - Normal subjectsB - Uraemic patients not

consuming Al medicationsC - UrQemic patients

consuming Al medications

....

A B C

Fig. 7 Serum aluminium (Al) in normal subjects and

subjects with chronic renal failure not treated bydialysis.

the Registry of the European Dialysis and TransplantAssociation found no correlation between oral intakeof aluminium hydroxide and incidence of dialysisencephalopathy.68 Tens of thousands of patientshave taken aluminium hydroxide to control plasmaphosphate in chronic renal failure without developingencephalopathy. Consequently it has now beengenerally assumed that the risk of dangerousaluminium overload from this source is small or

negligible.However there are a few disturbing facts that leave

a question mark over the safety of oral aluminium inrenal failure. One large outbreak of encephalopathyinvolved 13 patients who were dialysed against verylow concentrations of aluminium.1" This event was

so unusual that some other source of aluminiumoverload, not yet revealed by the careful investiga-tions at Nashville, must be suspected. Several otherisolated cases or small outbreaks have been attributed

to aluminium ingestion but must be accepted withsome reserve since the patients were dialysed againstfluid which contained 50-80 ,ug/l of aluminium39 69 orwas of unstated aluminium content.70 Even if thesecases are discounted as unproven, there remains ahard core of published cases which are difficult todismiss. At least four patients have developed"dialysis encephalopathy" without ever beingdialysed.7 71 72 In another patient, a rise in serumaluminium and the appearance of symptoms coin-cided with oral aluminium administration on twooccasions.73 In one outbreak encephalopathy stoppedoccurring, and affected patients improved, when oraladministration of aluminium was discontinued,without any reported change in dialysis conditions.70A few patients in Newcastle have developed veryhigh plasma aluminium concentrations after pro-longed administration of aluminium hydroxide forstable chronic renal failure. Different preparations ofaluminium hydroxide and other compounds differ intheir ability to bind phosphate74 or release alumin-ium.63 It is concluded that oral administration ofaluminium hydroxide is a rare cause of seriousaluminium overload and that patients in renalfailure receiving large doses over long periodsshould have regular checks of serum aluminium.

TreatmentThis disease is easier to prevent than to treat. Thebeneficial effects of transplantation at an early stagehave been mentioned above. Impressive reversal ofearly disease has been achieved also by rigorousexclusion of aluminium from the dialysis fluid andoral medications.41 However there was little to offerthe patient with well developed disease until theintroduction of chelation therapy by Ackrill and hiscolleagues.75 The effectiveness of desferrioxamine inremoving tissue aluminium has been confirmedindirectly by others59 but there are no published dataso far on direct tissue measurement, and onlypreliminary information on changes in cerebralfunction. The striking improvement in handwritingand other tests of constructional ability in patientswith moderately severe disease treated by removal ofthe source of aluminium45 gives ground for someoptimism.

ASSOCIATED FEATURES

Bone diseaseOsteomalacia, diagnosed histologically, affects about20% of patients in terminal renal failure.76 Ingeneral, treatment with regular haemodialysis andvitamin D analogues heals or improves most of thesepatients but it has become apparent in the last 13years that some dialysis centres were characterised

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1292by progressive development of a severe form ofosteomalacia causing bone pain, fractures, severe

deformity and myopathy, in which serum alkalinephosphatase was usually normal or low, serum

calcium was sometimes high and readily raised byadministration of calcium or vitamin D, and thebone lesion was unresponsive to vitamin D or itsnewer analogues. In Europe the disease has ba ome

known as "Newcastle bone disease" because of itshigh incidence in Northern England and our interestin the topic. Fuller descriptions of the syndrome, andthe evidence that it is caused by aluminium in bone,have been presented elsewhere.43 76-78 Two recentadvances in understanding have been the reproduc-tion of the disease in rats by aluminium administra-tion79 and the application of histochemical stains foraluminium, which have been verified by other tech-niques and which have shown aluminium localised inthe mineralising layer of the osteoid.80 It is now

possible to recognise the disease with some con-

fidence from a simple undecalcified bone biopsywithout the considerable effort required to measure

bone aluminium by neutron activation.Papers continue to appear from the United States

describing this form of bone disease and containingstatements like "the cause of this severe osteomalacia,which occurs despite normal or slightly elevated levelsof serum calcium and fails to mineralize with calci-triol, is unclear."81 It is suggested that the evidencepresented or reviewed in the articles quoted abovemakes it extremely likely that "this severe osteo-malacia" is another manifestation of aluminiumoverload.

AnaemiaPatients with dialysis encephalopathy are generallysick. They often lose weight and look ill. It is likelythat several tissues other than brain and bone are

affected. A microcytic anaemia is associated withdialysis encephalopathy4l 51 and remits when ex-

posure to aluminium is reduced.82 It may prove to bea useful early warning of the syndrome since in an

Edinburgh series it preceded clinical evidence ofbone disease and encephalopathy in many of thepatients.82

References

Alfrey AC, Mishell JM, Burks J, et al. Syndrome ofdyspraxia and multifocal seizures associated with chronichemodialysis. Trans Am Soc Artif Intern Organs 1972;18:257-61.

2Nadel AM, Wilson WP. Dialysis encephalopathy: a

possible seizure disorder. Neurologs' (N Y) 1976;26:1 130-4.

Mahurkar SD, Dhar SK, Salta R, Meyers L, Smith EC,Dunea G. Dialysis dementia. Lancet 1973;i:1412-5.

4Kerr DNS. Clinical and pathophysiologic changes in

Kerr, Parkinsoni, Wardpatients on chronic dialysis: the central nervous systenm.In: Maxwell MH, ed. Advances in nelphrolog.v. Vol 9.Medical Year Book Publishers, 1980:109-32.

Chui HC, Damasio AR. Progressive dialysis encephalo-pathy ("Dialysis dementia"). J Neiarol 1980;222:145-57.

6 Arieff Al. Neurological complications of uremia. In:Brennor BM, Rector FC, eds. The kidneY. Philadelphia:Saunders, 1981 :2306-43.

Kerr DNS, Ward MK, Parkinson IS. Dialysis enicephalo-pathy: questions and answers. In: Cumniings NB, ed.Proceedings of the Chronic Renal Disease Conference.NIH, 1980. Department of Health, Fducationand Welfare, 1981.

B3rratt LJ, Lawrence JR. Dialysis-associated dementia.Ault NZJ Mcd 1975;5:62-5.

Chokroverty S, Bruetman ME, Berger V, Reyes MIG.Progressive dialytic encephalopathy. ./ Ncorol Neuro.sugPvsrc.hiatrlv 1976;39:411-9.

Bone 1. Progressive dialysis encephalopathy. In: DavisoniAM, ed. Dialrsiv rvciva. TLinbridge Wells: Pitmani.1978:216-29.

" Dewberry FL, McKinney TD, Stone WJ. Tl e dialysisdementia syndrome: report of fourteen cases anid resie\sof the literature. ASAIO J 1980;3:10(2-8.

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Mamiurkar SD, Meyers L, Cohen J, Kamath RV, Dunea Ci.Electroencephalogranhic and radionuclide studies indialysis dementia. Kidtney Itnt 1978;13:306-15.

Silke B. Fitzg.crald GR, Hanson S, Carmody M. O'D\vyerWF. Dialysis dementia and renal transplantationi. DialTran splant 1978;7:486-7.

Sullivan PA, Murnaghan DJ, Callaghani N. Dialysisdemenitia: recovery after transplanitationi. Br ,.l(cdJ 1977:ii :740.

English A, Savage RD. Brittoni PG, Ward MK. KerrDNS. Intellectual impairment in chroniic renal failtirc.Br McdJ 1978;i:888-90.

1 Gilli P, Bastiani P, Rosati G, et al. limpairimienit of themental status of patients on regular dialysis treatimient.Pro: Eiar Dial Transplant Assoc 1980;17:306-11.

Ackrill P, Barron J, Whiteley S, Horn AC, Ralston AJ. Anew approach to the early detection of dialysis encephla-lopathy. Proc Eior Dial Transplant A.s.s ( 1979;16:659-60.

Cartier F, Chatel M, Allain P. Aluminiunm toxicity in renllafailure. In: Zurukzoglu W, Papadimitriou M, Pyrpaso-poulos M, Sion M, Zamboulis C, eds. Proceedings of theEighth International Congress of Nephrolog.r. Basle:Karger, 1981:1922-9.

20 Burks JS, Alfrey AC, Huddlestone J, Norenberg MD,Lewin E. A fatal encephalopathy in chronic haemo-dialysis patients. Lancet 1976;i:764-8.

21 Ward MK, Pierides AM, Fawcett P, et al. Dialysisencephalopathy syndrome. Proc Eotr Dial TransplantAssoc 1976;13:348-54.

22 Galle P, Chatel M, Berry JP, Menault F. Encephalopathiemyoclonique progressive des dialyses: presence d'alu-minium en forte concentration dans les lysosomes descellules cerebrales. Noave Presse Med 1979;8:4091-4.

23 Pierides AM, Ward MK, Kerr DNS. Haemodialysisencephalopathy: possible role of phosphate depletion.Lancet 1976;i:1234-5.

2' Rudolph H, Alfrey AC, Smythe WR. Muscle anid serumiltrace element profile in uremia. Trans An/ Soc ArtifIntern Organs 1973 ;19:456-61.

25 Alfrey AC, LeGendre GR, Kaehny WD. The dialysisencephalopathy syndrome. Possible aluminum intoxica-tion. N Engl J Med 1976;294:184-8.

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Requests for reprints to: Professor DNS Kerr, Depart-ment of Medicine, Royal Victoria Infirmary, Newcastleupon Tyne NEI 4LP, England.

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