Progressive dialytic encephalopathy - BMJ

Journal ofNeurology, Neurosurgery, and Psychiatry, 1976, 39, 411-419

Progressive dialytic encephalopathyS. CHOKROVERTY1, M. E. BRUETMAN, V. BERGER,

AND M. G. REYES

From the Department of Neurology, Mount Sinai Hospital Medical Center, Chicago,Neurology Service and Neurology Research Laboratory, Veterans Administration

Hospital, Hines, Illinois, USA

SYNOPSIS A subacutely progressive dialytic encephalopathy lasting for three to 15 months in 11patients who had been on haemodialysis for 14 to 36 months was characterized by dementia,language disorder, myoclonic jerks, behavioural disturbance, distinctive EEG abnormalities, andnormal or nonspecific neuropathological findings.

Since the introduction of successful extra-corporeal dialysis by Kolf and Berk (1966) andmaintenance haemodialysis by Scribner et al.(1960), the prognosis in terms of longevity forpatients with the end stage renal failure hasimproved considerably. Parallel improvementafter maintenance haemodialysis in metabolicderangements and the clinical manifestationshas been gratifying for patients, who weredestined to die within a short period of irrever-sible and inexorably progressive renal failurein the pre-dialysis era. However, it soon be-came apparent that long-term haemodialysishad its own hazards. Complications (Tyler,1965; Hampers and Schupak, 1967; Talalla etal., 1970; Bluemle, 1971; Lindner et al., 1974)related to the technical aspects of dialysis-metabolic bone disease, anaemia, haemosider-osis, pulmonary embolism, pericarditis, cardio-megaly, psychological problems, acceleratedatherosclerosis, subdural haematoma, andperipheral neuropathy have all been known.Dialysis disequilibrium, reverse urea syndrome,water intoxication, seizures, myoclonus, andtoxic psychosis have been frequently describedas temporary complications of haemodialysis(Tyler, 1965; Hampers and Schupak, 1967). Insome patients, prolonged confusional state maypersist for days (Tyler, 1965) but eventually

1 Present address: P.O. Box 127, Hines, Illinois 60141, USA.(Accepted 22 December 1975.)

the mental state reverts to the pre-dialyticstage. Furthermore, some patients in acuteand terminal stage of chronic renal failure andimmediately after dialysis (Tyler, 1965, 1968)develop confusion, disorientation, and con-vulsions progressing rapidly to coma anddeath. All these complications may be groupedunder the general heading of acute dialyticencephalopathy (ADE). This paper directsattention to a less well-documented subacutelyprogressive dialytic encephalopathy (PDE)(Alfrey et al., 1972; Mahurkar et al., 1973;Burks et al., 1974; Chokroverty et al., 1974).A characteristic clinical picture accompaniedby distinctive electroencephalographic (EEG)abnormalities emerged in 11 patients withchronic renal failure on long-term haemodialy-sis. Progressive dialytic encephalopathy in thesepatients, in contrast to patients with ADE oruraemic encephalopathy, did not depend eithersingly or in combination on rapid electrolyteshift, alteration of acid base balance, suddenrise of blood pressure, or increased levels ofblood urea nitrogen or creatinine.

REPORT OF CASES

All patients had been on maintenance haemo-dialysis using Ex-03 coil or Dow hollow fibredialyser three times a week for six hours eachtime. The dialysate was made up from commercialconcentrate with non-ionizing tap water.

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S. Chokroverty, M. E. Bruetman, V. P. Berger, and M. G. Reyes

CASE 1 A 55 year old woman with chronicglomerulonephritis had been on a long-termhaemodialysis programme for 18 months. Onemonth before admission she developed difficultyin speaking. Examination revealed an orientedwoman with nonfluent speech; her comprehensionwas good but she had difficulty in finding the rightwords. Additionally, her speech was character-ized by stuttering, mispronunciation, occasionalanomia, agrammatism, and impairment of repeti-tion. Her handwriting contained omissions andmisspelling of the words. The rest of the physicalexamination was unremarkable. Her speech im-proved somewhat and she was discharged homefive days later. She was readmitted five monthsafter discharge with agitated delirium, visual andauditory hallucinations, and paranoid delusions.After treatment with sedation and tranquillizers,her agitation subsided. During the last two weeksof her life she developed intermittent myoclonicjerks bilaterally, continued to have paranoid delu-sions, and remained demented and dysphasic. Shedeteriorated progressively and died seven monthsafter the onset of neurological disability.

CASE 2 A 47 year old woman had end stage renaldisease due to hypertension. She had been onmaintenance haemodialysis for 14 months. InAugust 1974 she developed myoclonic jerks in allfour limbs intermittently. At about the same timeshe had several transient attacks of nonfluentdysphasia. In the course of the next three weeksher speech became normal, myoclonic jerks im-proved considerably, and she was dischargedhome. In October 1974 she was readmitted be-cause of confusion, agitation, and inability tospeak. Neurological examination revealed markedagitation, disorientation, and non-fluent dysphasia.Motor and sensory testing demonstrated normalfindings and muscle stretch reflexes were sym-metrically present. Her mental status and langu-age problems showed day-to-day variation. On6 November 1974 she suddenly had a cardiacarrest. Despite resuscitative measures she re-mained deeply comatose and died on 11 Novem-ber 1974.

CASE 3 (Already published in detail by Mahurkaret al., 1973). Twenty-seven months after haemo-dialysis and bilateral nephrectomy, a 51 year oldwoman slowly became demented and later demon-strated grimacing, myoclonic jerks of limbs, dys-phasia, and dyspraxia. She became progressivelymore demented and died three months after theonset of neurological dysfunction.

CASE 4 A 25 year old man was admitted on 8July 1974 because of sudden onset of mutism andintermittent myoclonic jerks of face and limbsbilaterally for one week. He had been on a haemo-dialysis programme since July 1971 for chronicrenal failure and hypertension. Examination re-vealed a cooperative man who was able to under-stand commands but was completely unable totalk. There was lingual dyspraxia. His handwrit-ing, both spontaneously and while copying, dis-played omissions, misspellings, and perseveration.The rest of the neurological examination was nor-mal. In the course of the next 10 days his speechimproved and he was discharged with a mildstuttering dysarthria. On 28 August 1974 he againbecame completely mute and again the speechimproved in the course of the next 12 days. On16 September 1974 he had a violent myoclonicjerk which caused him to fall. Since then he hadbeen having intermittent myoclonic jerks of allfour limbs. In January 1975, myoclonic jerks be-came more frequent and he was unable to talk,although he tried to open his mouth and was ableto follow commands by mimicry. Two days laterhis speech returned spontaneously, myoclonicjerks became less frequent, and he was dischargedhome. He was readmitted on 5 May 1975 becauseof progressively increasing dementia, myoclonicjerks, agitation, and delusions. On 16 May 1975,after a sudden episode of hypotension, he died.

CASE 5 A 46 year old man, who had long-termhaemodialysis for chronic renal failure for 34months, was admitted because of sudden inabilityto talk. In the course of the next three days hisspeech returned but he was noted to have non-fluent dysphasia. His writing displayed persevera-tion, omission, and misspelling of words. Thelanguage problem would show periodic exacerba-tion and remission. Three months after the onsetof the neurological illness while having haemo-dialysis he had a transient episode of auditoryhallucination. Seven months after the onset of hisspeech difficulties, he developed intermittent myo-clonic jerks bilaterally which were made worse bynoise. He became progressively demented andincontinent of urine and faeces. He would respondto loud noises, light flashes, and pinching bybilateral myoclonic jerks. He died six months afterthe onset of the neurological dysfunction.

CASE 6 A 43 year old woman had been on main-tenance haemodialysis for hypertension, end stagekidney disease, and chronic renal insufficiency.She insidiously developed confusion, disorienta-

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Progressive dialytic encephalopathy

tion, impairment of memory, and 'abnormal be-haviour' while on chronic haemodialysis for 18months. Her mental functions would fluctuate andon some days she showed remarkable improve-ment. However, in the course of the next threemonths she developed myoclonic jerks of all fourlimbs intermittently and apraxia of gait. She be-came progressively more demented and died sixmonths after the onset of dementia.

CASE 7 Thirty-five months after long-termhaemodialysis for chronic renal failure, a 44 yearold woman developed myoclonic seizures. Perti-nent neurological findings consisted of diffusemyoclonic jerks and left homonymous hemianop-sia. Three months later she displayed intermittentconfusion. Seven months after the onset of myo-clonic seizures, she suddenly became mute. shewas able to comprehend and follow commandsbut was unable to speak or write. Her mutism wasgradually replaced by dysphasia which was charac-terized by inability to find the right words,hesitancy of speech, perseveration, and agramma-tism. Subsequently, she developed 'bizarre' be-haviour. She became agitated and pulled out herhair and eyebrows. Her mental functions pro-gressively deteriorated and she died seven monthsafter the onset of the myoclonic seizures.

CASE 8 After haemodialysis for 15 months forchronic renal failure, a 30 year old womandeveloped impairment of memory and bilateralmyoclonic seizures. Two weeks later she began toact in a strange manner and displayed delusion ofpersecution, auditory hallucination, disorientation,and inappropriate affect. Her behaviour improvedsomewhat but she remained severely demented,continued to have intermittent bilateral myoclonicseizures, and died three months after the onset ofthe neurological illness.

CASE 9 A 46 year old man had been on long-termhaemodialysis for three years for chronic glo-merulonephritis and renal failure. A renal trans-plantation was unsuccessful because of rejection.He gradually developed impairment of memory,intermittent confusion, disorientation, hallucina-tions, delusions, and periodic attacks of 'bizarre'behaviour. Six to seven months after the onset ofbehavioural and memory disturbance he beganintermittently to have frequent generalized tonic-clonic seizures and bilateral myoclonic jerks. Helater suddenly became dysphasic. He could com-prehend well but was unable to read, write, orrepeat words. His speech improved in the course

of the next few days but his mental functions con-tinued to deteriorate, myoclonic seizures becamemore frequent, and he died 15 months after theonset of dementia and 'bizarre' behaviour.

CASE 10 After haemodialysis for 15 months, a43 year old woman presented with 'bizarre' be-haviour, disorientation, impairment of memory,and paranoid delusions. She had had multiplehospital admissions for periodic exacerbations ofagitated delirium, hallucinations, and paranoiddelusions. Subsequently, she developed bilateralmyoclonic seizures, dysphasia, and dyspraxia anddied in status epilepticus three months after theonset of the neurological dysfunction.

CASE 11 A 40 year old woman had been onchronic haemodialysis for hypertension and renalfailure since March 1971. In December 1973, dur-ing haemodialysis, she had a transient loss of con-sciousness and twitching of the mouth and hadbitten her tongue. After this episode, her mentalfunctions progressively became impaired. InMarch 1974, she was admitted in a mute state. Shecould not follow written commands, could notwrite, but was alert and able to mimic well. Ad-ditional pertinent neurological findings includedfoot grasp, snout reflex, and diminished anklejerks bilaterally. While in the hospital she devel-oped bilateral myoclonic jerks. Her spontaneousspeech had returned one or two days afteradmission but her speech and writing were charac-terized by perseveration, hesitancy, misspelling,and omission of words. She also had right-left dis-orientation and dyscalculia. On the fourth hospi-tal day she suddenly became very agitated andstarted shouting that someone was trying to killher. Her paranoid delusions and agitation per-sisted and she suddenly died on the sixth hospitalday.

LABORATORY DATA In nine patients the range ofvalues for blood urea nitrogen, serum creatinine,sodium, potassium, calcium, phosphorus and albu-min, and blood pH during one year before theonset of PDE and during the period of neurologi-cal dysfunction did not show any significant over-all changes. Except for slightly low protein incases 5-7, the cerebrospinal fluid, examined inseven patients, was normal. Brain scan (cases 1, 2,10), cisternal scan (cases 2, 6, 8, 9), cerebral angio-gram (case lI) and pneumoencephalogram (case 9)gave normal results.

EEG STUDY Bipolar and referential recordings ofthe EEGs were obtained in all patients on an 8-

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or 16-channel electroencephalograph, using theInternational 10-20 electrode placement system.During some portion of the recording, EEG re-sponses after clapping, pinching of the extremi-ties, and eye opening and closing were noted. TheEEG findings are summarized in Table 1. Thedominant EEG rhythm consisted of 8-10 Hzactivity in all except cases 5 and 7. An excessiveamount of theta rhythm was present in sixpatients (cases 2, 4-8). All patients demonstratedbisynchronous, mostly anteriorly dominant, inter-

mittent rhythmic delta waves in the majority ofthe tracings (Fig. 1). The second most commonEEG manifestation was the presence of fronto-central spike-and-slow wave complexes in a bi-laterally synchronous fashion (Fig. 2). Theseepileptiform activities were present predominantlyon the left side in case 5, on the right in case 7,and more or less symmetrically in the remainingcases. Photic stimulation (cases 3-6, 9, 11) acti-vated the epileptiform activities in four patients(cases 3-5, 9). Two patients (cases 2 and 5) demon-

TABLE 1EEG DATA IN PATIENTS WITH PROGRESSIVE DIALYTIC ENCEPHALOPATHY

Case Dominant Bisynchronous Frontocentral Sleep spindles Otherrhythm rhythmic delta spike-and-slow(Hz) (Hz) waves

19 3 SmerclNone2 8-9 2.5-3 }Occasional }ymmetrica Excess 5-6 Hz. Triphasic waves3 8 2-3 No sleep None4 9-10 3 }Frequent Excess 5-6 Hz5 7-8 3 Symmetrical Excess 5-6 Hz. A few triphasic waves6 8 2-3 None Excess 5-7 Hz7 7-8 2.5-3 Occasional Excess 5-6 Hz8 8 2-3 None No sleep Excess 5 Hz9 9-10 2-2.5 Symmetrical None10 8 2-3 SFrequent No sleep11 9 2-3 Symmetrical Excess fast rhythms

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FIG. 1 Case 9. EEG. Bisynchronous anteriorly dominant intermittent rhythmic delta waves whileawake.

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Progressive dialytic encephalopathy 415

FPI-F7

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FIG 2 Case 9. EEG while awake. Frontocentral spike-and-slow waves andanteriorly dominant rhythmic delta waves seen bisynchronously.

strated triphasic waves during some part of the (end stage) kidneys. Case 3 had bilateral nephrec-recording (Fig. 3). Pre-and post-dialysis EEGs did tomy. In case 9 the left kidney was polycystic andnot show any significant variation in our patients. the right kidney was absent (post-nephrectomy).

Patient IO had end stage left kidney and hypo-PATHOLOGICAL OBSERVATIONS General post- plastic right kidney.mortem examination performed in seven patients(cases 1-4, 9-11) showed left ventricular hyper- NEUROPATHOLOGICAL FINDINGS Neuropathologicaltrophy and congested liver in all patients. In cases examination of the central nervous system in cases1, 2, 4 and 11 there were bilateral contracted 1, 4, 9, and 10 revealed normal findings. In case 2,



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FP1-F7 _

F 7- T 3

T3-T5 _ Jm,

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FIG. 3 Case 2. EEG. Anteriorly dominant bilateral triphasic waves.

multiple lacunae were noted bilaterally in the dor-somedial, ventral, and the right reticular nucleusof the thalamus, caudate nucleus, putamen, andthe right insular cortex. In addition, there wereanoxic-ischaemic changes in the cerebral, cere-bellar, and subcortical neurones.

Macroscopic examination of the brain in case 3was normal. Microscopically, there was an oldlacunar infarction in the right putamen.

In case 1 1, macroscopic examination of thebrain was normal. Microscopically, there werelacunar infarcts bilaterally in the putamen and inthe periaqueductal grey region of the midbrain.

DISCUSSION

CLINICAL ANALYSIS An analysis of the clinicalfeatures in these 11 patients revealed that themajor manifestations of PDE can be groupedunder four headings: (1) dementia; (2) lan-guage disorders; (3) myoclonic jerks, and (4)behavioural disturbances. These four features,the PDE tetrad, were present in seven patients(cases 1, 2, 4, 7, 9-11). Three manifestations ofthe tetrad were present in all patients, andtherefore we believe that the term 'progressivedialytic encephalopathy' describes the entity

more appropriately than the term 'dialysisdementia'. One notable feature was the peri-odic fluctuation but always inexorable pro-gression of the disease.

DEMENTIA This symptom was present in allpatients. The main manifestations in thesepatients were confusion, disorientation, im-pairment of memory, and later behaviouraldisturbances. Progressive dialytic encephalo-pathy began with dementia in six patients(cases 3, 6, 8-11). Patient 4 developed demen-tia terminally.

LANGUAGE DISORDER This was characterizedby mutism or global dysphasia with dominantdifficulty in expression. Language dysfunctionwas the principal feature at the onset of PDEin four patients (cases 1, 2, 4, 5) and waspresent in course of the illness in all patientsexcept in cases 6 and 8.

MYOCLONIC JERKS These were noted in allpatients in the course of PDE and were theprincipal manifestations in the beginning of

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the illness in four patients (cases 2, 4, 7, 8).Myoclonic jerks were present bilaterally andsometimes were stimulus sensitive.

BEHAVIOURAL DISTURBANCES These symptomswere characterized by agitation, delirium,paranoid delusions, hallucinations, and some-times by 'bizarre' behaviour. These werepresent in all patients and were the majormanifestations at the onset of PDE in fourpatients (cases 6, 8-10).

In the initial period of our study (Chokro-verty et al., 1974), it appeared that PDE pro-bably progressed through three distinct stages.However, as more and more patients were ob-served over a period of time, we could notconfirm our original impression as PDE mani-fested itself with the aforementioned tetrad invarying combination without passing throughany distinct clinical stages. In our series, PDEbegan 14 to 36 months after maintenancehaemodialysis and lasted from three to 15months.

It is obvious from the above clinical analysisthat any or all of the PDE tetrad may bepresent in uraemic encephalopathy in additionto focal sensory-motor deficits or seizures.However, there are distinct differences be-tween the manifestations of PDE and uraemicencephalopathy and these are summarized inTable 2. According to Curtis et al. (1969), twoto three periods of haemodialysis each weekmay not achieve the normal renal regulatoryfunctions and, despite maintenance haemo-dialysis, these patients continue in a state of

uraemia. Therefore, progressive dialytic en-cephalopathy would appear to be a variant ofuraemic encephalopathy but with an alteredcourse and related in some as yet unknownway to maintenance haemodialysis. Whetherby increasing the frequency of dialysis the out-come of PDE could be altered or the patientsbecame truly refractory to dialysis cannot bedetermined from our study. However, Burkset al. (1974) stated that more frequent dialysisdid not alter the clinical course in theirpatients.

ELECTROENCEPHALOGRAPHY Normal or mild-to-moderate slowing of the background EEGactivity intermixed with frontally dominantintermittent rhythmic bisynchronous deltawaves and frontocentral epileptic-type activi-ties in patients with PDE were not specific butwere characteristically noted in all patientsduring some stage of the illness. Similar EEGchanges are known to occur in patients withuraemic or other metabolic encephalopathies(Cadilhac and Ribstein, 1961) and most pro-bably indicate functional derangement of cor-tical and reticulocortical neurones. However,we did not observe appropriate anatomicalalterations to account for dysfunction of cor-tical and reticulocortical neurones on neuro-pathological examination of the brain.

NEUROPATHOLOGICAL ASPECTS A survey of theliterature reveals that the neuropathologicalchanges in uraemic brain (Olsen, 1961) consistin variable combinations of neuronal degenera-

TABLE 2COMPARISON OF SALIENT FEATURES BETWEEN PROGRESSIVE DIALYTIC ENCEPHALOPATHY (PDE) AND URAEMIC

ENCEPHALOPATHY

Onset and relation to dialysis PDE after prolonged haemodialysis Uraemic encephalopathy after end stagekidney disease. Improves after dialysis

Course Subacute AcuteDuration of illness 3-15 m Days to weeksRelation to systemic biochemical changes No definite relationship noted Usually relatedAssociated cerebrovascular disease None FrequentEEG Non-specific but distinctive (bisynchronous Non-specific and variable (diffuse and focalrhythmic delta and frontocentral slowing, spike-and-slow waves,spike-and-slow waves) photosensitivity, and paradoxical alpha

attenuation)Neuropathological data None significant. Sometimes lacunae in brain Variable combination of cerebral oedema,infarction, and haemorrhage. Non-specificloss of cortical and reticular neurones

B

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tion, foci of softening, astrocytic proliferation,vascular damage, petechiae, focal demyelina-tion, cerebral oedema, toxic encephalitis, andnecrosis of the granular layer of the cerebellarcortex. We found none of these changes in ourpatients except lacunae in the basal gangliaand thalamus in cases 2, 3, and 11. Theselacunar infarcts cannot be responsible for thePDE tetrad and the EEG findings. Therefore,a marked disparity between the clinical and theneuropathological observations is very charac-teristic of the entity of PDE.

PATHOGENESIS Absence of morphological cor-relates for the clinical observations would tendto favour a possible metabolic cerebral dys-function. However, as stated previously, therewere no overall changes in the systemic bio-chemical parameters from the values notedbefore the onset of PDE. Therefore, it is prob-lematical to ascribe the neurological illness tometabolic encephalopathy caused by alteredsystemic metabolism but there may be a pos-sible relationship between PDE and uraemicencephalopathy as discussed above in theclinical analysis.The group of investigators from Colorado

(Alfrey et al., 1972; Burks et al., 1974) noteda high concentration of tin and decreasedrubidium in the brains of seven patients withprogressive dialytic encephalopathy. As thereis no evidence of a significant role for rubidiumin human health, these workers suggestedtin as a possible aetiological factor in thistype of encephalopathy. Although tin is knownto cause an encephalopathy in animals andman (Torack et al., 1960; Alajouanine et al.,1958; Prull and Romple, 1970), the charac-teristic PDE tetrad, the distinctive EEGchanges, absence of cerebral oedema (Toracket al., 1960) in our patients, the observationsof high tin content in uraemic patients with-out encephalopathy (Alfrey et al., 1972), andthe normal concentration of tin in the brainof at least one of our patients (Chokrovertyet al., 1974) would speak against tin as anaetiological factor in PDE.

Finally, suggestion of possible dopamine(Wardle, 1973) or asparagine (Gunale, 1973)deficiency or any other cerebral neurochemical

defect in PDE is pure speculation but mayform a theoretical basis for a future line ofinvestigation. At present, the aetiology ofprogressive dialytic encephalopathy remainsunknown.

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Alfrey, A. C., Mishel, J. M., Burks, J., Contiguglia,S. R., Rudolph, H., Lewin, E., and Holmes, J. H.(1972). Syndrome of dyspraxia and multifocalseizures associated with chronic hemcdialysis.Transactions of the American Society of ArtificialInternal Organs, 18, 257-261.

Bluemle, L. W., Jr (1971). Dialysis. In Diseases of theKidney, vol 1, pp. 343-371. Edited by M. B. Straussand L. G. Welt. Little, Brown: Boston.

Burks, J., Huddlestone, J., Lewin, E., Alfrey, A.,and Rudloph, H. (1974). A progressive encephalo-pathy in chronic dialysis patients. (Read before theAmerican Academy of Neurology, San Francisco,1974). Neurology (Minneap.), 24, 359.

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Gunale, S. R. (1973). Dialysis dementia: asparaginedeficiency? Lancet (Letter to editor), 2, 847.

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Lindner, A., Charra, B., and Sherrard, D. (1974). Ac-celerated atherosclerosis in prolonged maintenancehemodialysis. New England Journal of Medicine,290, 697-706.

Mahurkar, S. D., Dhar, S. K., Salta, R., Meyers,H. L., Jr, Smith, E. C., and Dunea, G. (1973).Dialysis dementia. Lancet, 1, 1412-1415.

Olsen, S. (1961). The brain in uremia. Acta Psychi-atrica et Neurologica Scandinavica, suppl 156, 36,1-128.

Prull, G., and Romple, K. (1970). EEG Changes inacute poisoning with organic tin compounds.

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(1960). The fine structure of cerebral fluid accumu-lation. 2. Swelling produced by triethyl tin poison-ing and its comparison with that in the humanbrain. American Journal of Pathology, 36, 273-287.

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