DIALYSIS DEMENTIA

1412

kidneys to rats made nephrotic by injection of puromycin aminonucleoside did not transfer the disease; protein excretion of the transplanted kidneys did not increase. However, kidneys from nephrotic rats transplanted to normal rats did transfer the disease. These recipients had massive proteinuria even when exposure to aminonucleoside

was

limited

to

the trans-

planted kidney.’ Thus, in both c.N. and aminonucleoside nephrosis in rats, the basic abnormality leading to massive proteinuria appears to reside within the kidney, rather than to depend on systemic influences. The immunofluorescent-microscopy studies we report accord with previous reports and suggest that immunological injury does not appear to be a primary factor in pathogenesis of C.N.5,8,9° In initial biopsy specimens, IgM and IgG were observed only within the glomerular mesangium. Studies of rats with aminonucleoside nephrosis indicate that in the presence of proteinuria there is increased uptake of immunoglobulin macromolecules by the glomerular mesangium.100 Such changes in mesangial function in proteinuric states could explain the focal mesangial deposition of immunoglobulin, predominantly IgM, observed in renal tissues, both in the patients we report and in the idiopathic nephrotic syndrome.1a Attempts to treat children who have neonatal c.N. with corticosteroids or agents such as azathioprine or cyclophosphamide have been uniformly unsuccessful. However, in a few cases of nephrotic syndrome with onset at 3 to 6 months of age, treatment with cyclophosphamide or intravenous corticotrophin was associated with pronounced decrease in proteinuria. 5,12,13 Furthermore, remission of nephrotic syndrome has been observed in infants with congenital syphilis after appropriate antibiotic therapy. Therefore, it is important that as precise a diagnosis as possible be established before making major therapeutic decisions. Children with c.N. have severe growth failure. However, growth to 15 lb. or more (dry weight) is in our experience sufficient to allow the transplantation Careful medical of kidneys from adult donors. management of patients with c.N., including vigorous specific therapy of infections, is required to allow survival of these infants until transplantation. We have found that intensive long-term oral diuretic therapy has enabled these patients to remain almost completely free of oedema; thus the respiratory and infectious complications that are in large part secondary salt and water retention have been minimised. The absence of proteinuria after transplantation indicates that this procedure may successfully cure this disease. In view of the regular occurrence of growth failure, decreased resistance to infection, and the

to

invariable mortality during early childhood, transplantation may be indicated in these patients before renal failure develops. Although the ultimate prognosis for any young child after renal transplantation is uncertain, this therapy offers the only hope for patients with this otherwise invariably fatal disease. J. R. H. is a special postdoctoral fellow of the National Institutes of Health. This work was supported by grants from the National Institutes of Health.

Requests for reprints should be addressed to R. L. V., Medical School, Box 491, Mayo Memorial Building, University of Minnesota, Minneapolis, Minnesota 55455, U.S.A.

REFERENCES

Michael, A. F., Drummond, K. N., Good, R. A., Vernier, R. L. J. clin. Invest. 1966, 45, 237. 2. Norio, R. Annls Pœdiat. Fenn. 1966, 12, suppl. 27. 3. Hallman, N., Norio, R., Kouvalainen, K., Vilska, J., Kojo, N. Ergebn. inn. Med. Kinderheilk. 1970, 30, 3. 4. Worthen, H. G., Vernier, R. L., Good, R. A. Am. J. Dis. Child. 1959, 98, 731. 5. Hoyer, J. R., Michael, A. F., Good, R. A., Vernier, R. L. Pediatrics, Springfield, 1967, 40, 233. 6. Hoyer, J. R., Raij, L., Vernier, R. L., Simmons, R. L., Najarian, J. S., Michael, A. F. Lancet, 1972, ii, 343. 7. Hoyer, J. R., Ratte, J., Potter, A. H., Michael, A. F. J. clin. Invest. 1972, 51, 2777. 8. Rapola, J., Savilahti, E. Acta pœdiat. scand. 1971, 60, 253. 9. Griswold, W., McIntosh, R. M. J. med. Genet. 1972, 9, 245. 10. Mauer, S. M., Fish, A. J., Blau, E. B., Michael, A. F. J. clin. Invest. 1972, 51, 1092. 11. Roy, L. P., Westberg, N. G., Michael, A. F. Clin. expl Immun. (in the press). 12. Fujiwara, T., Kikuchi, N., Shibuya, T., Kusakabe, I., Aida, M. Tohoku J. exp. Med. 1962, 75, 319. 13. Wiggelinkhuizen, J., Kaschula, R. O., McDonald, R., Uys, C. J, S. Afr. med. J. 1972, 46, 684. 1.

Addendum

Since

preparation of this report we have successfully transplanted a maternal kidney to a fourth child with congenital nephrosis. This 3-year-old girl now has a normal serum-creatinine (0-3 mg. per 100 ml.) and has not had significant proteinuria in the 2t months since transplantation.

DIALYSIS DEMENTIA SAKHARAM D. MAHURKAR RAUL SALTA EARL C. SMITH

SISIR K. DHAR LEE MEYERS, JR. GEORGE DUNEA

Departments of Nephrology and Neurology, Cook County Hospital, Mount Sinai Hospital Medical Center, and University of Health Sciences, Chicago Medical School, Chicago, Illinois, U.S.A. A fatal neurological syndrome characterised by progressive dementia, dyspraxia, facial grimacing, and myoclonus developed in two patients maintained by hæmodialysis for more than 2 years. The ætiology of this syndrome is unknown.

Sum ary

Introduction

A FATAL and mysterious neurological syndrome has been recognised in patients maintained on long-term hsemodialysis.1 It consists of progressive dementia, dyspraxia, bizarre involuntary movements, facial

grimacing, myoclonus, and characteristic electroencephalographic changes. We describe two patients who represent examples of this syndrome. Case-reports FIRST CASE

42-year-old Black woman with benign essential hypertension and nephrosclerosis was placed on maintenance haemodialysis at Cook County Hospital in December, 1969. Hypertension became difficult to control and a bilateral nephrectomy was performed in July, 1972. She continued to be dialysed for 6 hours three times a week with an EX-03 coil or Dow hollow-fibre dialyser, using A

commercial

concentrate

and tap-water without deionisers.

1413 In

September, 1972, episodes of stuttering speech with

articulate words, and intention Her memory became impaired, she tremor developed. became disoriented, and at times she had hallucinations. At first these episodes were brief, later they became more prolonged and frequent. She also had two grand-mal seizures. Neurological examination disclosed no signs of meningeal irritation. She was confused and disoriented, her speech was incoherent with perseveration, she was apraxic and could not recognise objects or obey commands. She moved all four limbs simultaneously, particularly in response to painful stimulation, and had bizarre myoclonic jerks. Reflexes were brisk, with sustained ankle clonus on the right and occasionally on the left, and with occasional adductor spasms at the hip, but no focal neurological deficit. Fundi showed sclerotic vascular changes. Bloodpressure was 140/90 mm. Hg. Cerebrospinal fluid (c.s.F.) pressure was 150 mm. Hg

facial grimacing, inability

to

and the fluid was clear and acellular; the protein level was 90 mg. and glucose was 54 mg. per 100 ml. c.s.F. chlorides were 110 meq. per litre (normal range 115-130 The packed-cell volume was 20%. meq. per litre). Predialysis urea and creatinine levels, serum electro-

lytes, glucose, phosphorus, magnesium, proteins, alkaline phosphatase, lead, folate, and vitamin-B12 levels were unremarkable. Skull X-rays were normal; the brain scan showed a slightly increased isotope concentration in the left periphery, but the left carotid angiogram was normal. The electroencephalogram (E.E.G.) (fig. 1) showed diffuse (5-7 per second) multifocal delta waves interrupted by bilaterally synchronous, high-voltage complexes consisting of slow, sharp, triphasic and sometimes spike waves. These were synchronous in both hemispheres, predominantly frontoparietal and near the midline, with fluctuating random asymmetry. The record was suggestive of a metabolic encephalopathy, myoclonic epilepsy, or

Fig. 1-Itepresentative segment

of E.E.G. of

case

1.

1414

Fig. 2-Representative segment of

with diazepam and total dementia and became incontinent, unable to eat, and led a vegetative existence. Dialysis was discontinued in December, 1972. Permission for necropsy was refused.

myoclonus. She was treated imipramine, but she progressed to

E.E.G. of

case

Discussion

status

SECOND CASE

A 51-year-old Black woman with malignant hypertension had been maintained by hxmodialysis at Mount Sinai Hospital since April, 1970. She received three 6-hour dialyses per week, using an EX-03 coil dialyser. The dialysate was made up from commercial concentrate with non-deionised tap-water. Her kidneys were removed in October, 1971. In September, 1972, stuttering speech, facial grimacing, muscle weakness, twitching, and a confusional state developed. Physical examination revealed dyspraxia, bizarre athetotic movements, reduced deeptendon reflexes, and proximal muscle weakness. Cranial nerves and sensory examination were normal. Bloodwas her was mm. heart 180/116 pressure Hg, enlarged, and the fundi showed moderate arteriosclerotic changes. The packed-cell volume was 14%. Serum urea, creatinine, uric acid, electrolytes, calcium, phosphorus, magnesium, lead, and proteins were unremarkable. The C.S.F. was clear and under normal pressure. There were 6 cells per c.mm., the protein was 83 mg. per 100 ml., and the glucose 59 mg. per 100 ml. c.s.F. chlorides were 129 meq. per litre. Cultures of C.S.F. were sterile and no fungi or organisms were seen. Brain scan was normal. The E.E.G. (fig. 2) record was diffusely slow with prominent 5-6 cycles per second activity and with paroxysmal, diffuse, rhythmical bursts of high-voltage delta activity which were of higher voltage and sharper quality over the bifrontal region. Occasional spike components were seen, together with paroxysmal bursts of delta activity. In the hospital she became more confused, severe apraxia developed, and facial grimacing increased. Adding urea to the dialysis bath and decreasing the dialysis time to 3 hours produced no improvement. Dimercaprol was given twice before dialysis without improvement. The patient gradually deteriorated, refused to eat, became comatose and hypotensive, and died in October, 1972. The necropsy showed no gross or microscopic abnormalities in the brain.

2.

Some of the neurological complications encountered in end-stage renal failure are caused by uraemia, electrolyte imbalance, or hypertension.2 Others arise from the therapy. Seizures may occur during dialysis; the declotting of shunts may result in cerebral emboli 3; subdural hxmatomas are related to heparinisation 4; and disequilibrium is caused by too rapid dialysis.. After transplantation and immunosuppressive therapy cerebral tumours may develop. 6 The syndrome we describe is a slowly progressive dementia with speech disturbances, involuntary movements, myoclonic jerks, and multifocal seizures, arising in well-dialysed patients who had no biochemical abnormalities of overt uraemia. The symptoms were not improved by dialysis, and in the case reported by Alfrey et al. actually became worse after each treatment. The E.E.G. changes are abnormal and distinctive. The aetiology of this disorder is not known. Disequilibrium cannot be incriminated, because the condition has occurred with rapid as well as with slow dialysis. One of our patients was dialysed against a high-urea concentration dialysate without effect on the clinical status. We found no evidence of spaceoccupying lesions, and the histological findings in case 2 were normal. Neither can vitamin deficiency be implicated, because our patients had adequate supplementation. No deionisers were used in any of these cases.

Tin poisoning has been incriminated in the aetiology of this encephalopathy, because trace-metal analysis demonstrated high tin levels in the brain tissue of I some patients. However, the increased tin levels were better correlated with the length of time on dialysis than with the neurological symptoms. Neither could other metals such as rubidium, potassium, or magnesium be implicated, and thus the xtiology of this disorder remains undetermined. Requests

for

reprints should be addressed

to

G. D., Cook

1415 County Hospital, 1825 West Harrison Street, Chicago, Illinois 60612, U.S.A. REFERENCES

Patients and Methods

Patients Case 1.-A 44-year-old woman with a 10-year history of and several recurrent episodes of, exacerbation. On her sixth admission to the Massachusetts General Hospital she developed a gram-negative septicxmia complicated with pulmonary embolism and died. Necropsy was performed within 2 hours of death. M.S. plaque and periplaque areas of the brain were supplied by Dr David Poskanzer. Case 2.-A 32-year-old woman with a well-documented diagnosis of M.S. was admitted to the University of MinneA sota Hospital for stereotaxic surgery (thalamotomy). piece of the white matter was obtained during surgery and supplied to our laboratory by Dr Howard Reid. Case 3.-A 48-year-old woman with signs and symptoms of M.S. for 15 years was admitted to the Bird Colar Hospital, New York, during an exacerbation episode. Shortly after her admission severe pneumonia developed and she died. Necropsy, performed 4 hours after death, revealed typical M.S. plaque in white matter of both hemispheres. Tissue samples were provided by Dr David Sohn. M.S.

1.

2. 3.

4. 5. 6.

Alfrey, A. C., Mishell, J. M., Burks, J., Contiguglia, S. R., Rudolph, H., Lewin, E., Holmes, J. H. Trans. Am. Soc. artif. intern. Org. 1972, 18, 212. Tyler, H. R. Am. J. Med. 1968, 44, 734. Gaan, D., Mallick, N. P., Brewis, R. A. L., Seedat, Y. K., Mahoney, M. P. Lancet, 1969, ii, 77. Leonard, C. D., Weil, E., Scribner, B. H. ibid. p. 239. Rosen, S. M., O’Conner, K., Shaldon, S. Br. med. J. 1964, ii, 672. Schneck, S. A., Penn, I. Lancet, 1971, i, 983.

VIROLOGICAL STUDIES WITH MULTIPLE-SCLEROSIS BRAIN TISSUES LUIZ H. BARBOSA

REBECCA HAMILTON

Infectious Diseases Branch, Collaborative and Field Research, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland, U.S.A. Tissue-cultures were prepared from brain tissues of three patients with multiple sclerosis (M.S.). The original brain specimens, the tissue-cultures, and co-cultivated brain cultures were extensively tested for the possible presence of viruses by several methods, including immunofluorescence, electron microscopy, hæmadsorption, cocultivation with several different cell cultures, and There biochemical " shocking " with idoxuridine. was no evidence of an infectious agent. However, electron microscopy revealed intracytoplasmic herringbone-like structures in glial cells of one of the specimens, similar to those previously observed in amyotrophic-lateral-sclerosis, scrapie, and kuru brain cells. Serological tests for measles and parainfluenza type-1 antibodies were performed on serum and cerebrospinal-fluid (C.S.F.) samples from twenty-five M.S. patients and twenty-five matched controls. Two M.S. patients had parainfluenza type-1 antibodies in their C.S.F. and three M.S. C.S.F. samples contained measles antibodies, while none of the C.S.F. control specimens yielded detectable antibody levels to either of these agents. There was no significant difference between serum titres against these viruses in the M.S. group and in the controls.

Summary

Introduction

SEVERAL human subacute and chronic neurological diseases are suspected of having a viral aetiology. Some clinical, pathological, and immunological studies have suggested a possible association between measles virus and multiple sclerosis (M.S.).l-lO An infectious agent related to parainfluenza type-1 virus was isolated from cultured brain cells of two M.S. cases." Although none of these reports presented conclusive evidence to implicate either measles or parainfluenza viruses as the causative agent of M.S., they warrant

investigation. We have

performed

various

virological

tests

on

tissue-cultures prepared from brain cells obtained from three M.s. patients. Serological tests on twenty-five M.S. and matched control cerebrospinal-fluid (c.s.F.) and

serum

samples

were

also

performed.

Methods The techniques for the preparation of primary explant brain cultures and subcultures have been described elsewhere.12 Co-cultivation of the brain cells with other cells has also been described.13 Primary and secondary M.S. brain cultures were each separately co-cultivated with hela, Wl-38, McCoy, African green-monkey kidney (A.G.M.K.), and human embryonic kidney (H.E.K.) cells. All brain cultures and mixed cultures were incubated at 37 °C in an atmosphere of 5% carbon dioxide in air. Human type-0, rhesus monkey, guineapig, chick, and sheep red-blood cells were used for hasmagglutination (HA) and haemadsorption (HAd) tests. The haemadsorptioninhibition (HAdI) and haemagglutination-inhibition (H.I.) tests were conducted according to standard procedures.14 The H.I. and HAdI assays were performed with serum and C.S.F. samples from twenty-five M.S. patients and twentyfive matched controls with neurological diseases other than M.S. The controls included the following patients: two GuiIlain-Barré; three subacute sclerosing panencephalitis (S.S.P.E.); two amyotrophic lateral sclerosis (A.L.S.); two

Creutzfeldt-Jakob; two hypertrophic spine; two epilepsy; cervical radiculitis; two cervical spondylosis; two myelopathy ; one cervical myositis; four herniated disc; and one encephalopathy of unknown aetiology. Controls were matched for race, sex, and age (within 4 years). Measles and parainfluenza type-1 Sendai antigens for these tests were prepared in our laboratory by previously reported one

methods. 144 Brain cultures and mixed cultures were tested by the indirect immunofluorescent (F.A.) assay in the presence of homologous and heterologous M.S. sera. The F.A. technique is described elsewhere. 15 Attempts to activate a defective or unexpressed virus genome by treatment of the brain cultures with idoxuridine (l.U.D.R.) was carried out as described by Lowy et al.16 For electron-microscopic examinations of the brain specimens and tissue-cultures the cells were processed as described by Horta-Barbosa et al.13 The samples were fixed in methanearsonic-acid-buffered 2% glutaraldehyde, postfixed in Dalton’s chrome-osmium, and embedded in Epon ’ before being sectioned and doubled stained with uranyl acetate and lead citrate. ,

Results

Brain Specimens Electron

microscopy

did

not

show evidence of viral