DEVELOPMENTAL MEDICINE A N D CHILD NEUROLOGY. 198 1,23

Acknowledgements: This study was supported in part by Research Grant HD12626 and Training Grant 5- T32HW7040 from the National Institute of Child Health and Human Development, and by a United Cerebral Palsy-J. William Hillman Graduate Student Fellowship (Grant no. SF-3-78 to JLK).

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5.

6.

7 .

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13. 14.

IS.

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18.

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20.

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REFERENCES I . Hagberg, B., Olow. I., Hagberg, G. (1973) ‘Decreasing incidence of low birth weight diplegia-

an achievement of modern neonatal care?’ Acta Paediatrica Scandinavica. 62. 199-200. 2. Hagberg, B., Hagberg, G., Olow, I . (1975) ‘The changing panorama of cerebral palsy in Sweden,

1954-1970. I: Analysis of the general changes.’ Acta Paediatrica Scandinavica. 64, 187-192. Hagberg, B., Hagberg, G., Olow. I. (1975) ‘The changing panorama of cerebral palsy in Sweden,

1954-1970. 11: Analysis of the various syndromes.’ Acta Paediatrica Scandinavica. 64, 193-200. Hagberg, B., Hagberg, G., Olow, 1. (1976) ‘The changing panorama of cerebral palsy in Sweden,

1954-1970. Ill: The importance of fetal deprivation of supply.’ Acta Paediatrica Scandinavica. 65, 403408.

Hook, E. (1981) ‘Incidence and prevalence as measures of the frequency of birth defects.’ Paper presented at the 14th Annual Meeting of the Society for Epidemiologic Research. Snowbird. Utah, 18th June. 1981.

Usher, R . ( 1963) ‘Reduction of mortality from respiratory distress syndrome with early administration of intravenous glucose and sodium bicarbonate.’ Pediatrics. 32,966-975.

Hagberg. B. ( 1978) ‘The epidemiological panorama of major neuropediatric handicaps in Sweden.’ I n Apley. J . (Ed.) Care of the Handicapped Child. Clinics in Developmental Medicine. No. 67. London: S.I.M.P. with Heinemann Medical; Philadelphia: Lippincott. pp. I 11-124.

Hagberg, B. (1979) ‘Epidemiological and preventive aspects of cerebral palsy and severe mental retardation in Sweden.’ European Journal of Pediatrics. 130, 71-78.

Glenting, P. (1976) ‘Variations in the population of congenital (pre and perinatal) cases of cerebral palsy in Danish counties east of the Little Belt during the years 1950-1969.’ Llgeskrift for Laeger. 138. 2984-2991.

Kaern, T. (1978) ‘Congenital cerebral palsy. I: Quantitative circumstances, illustrated from the patients of a single department of obstetrics, 1956-1973.’ Danish Medical Bulletin. 25, 137-140.

Woods, G . E. ( 1963) ‘A lowered incidence of infantile cerebral palsy.’ Developmental MedicineandChild Neurology, 5,449-450.

Griffiths, M. I . , Barrett, N. M. (1967) ‘Cerebral palsy in Birmingham.’ Developmental Medicine and Child Neurology.. 9, 33-46.

Gudmundsson, G. ( 1967) ‘Cerebral palsy in Iceland.’ Acta Neurologica Scandinavica. Suppl. 34. Nelson, K . B., Ellenberg, J. H. (1978) ‘Epidemiology of cerebral palsy.’ Advances in Neurology. 19, 419-432.

Stanley, F. J. (1979) ‘An epidemiological study of cerebral palsy in Western Australia, 1956-1975. I: Changes in total cerebral palsy incidence and associated factors.’ Developmental Medicine and Child Neurology. 2 I , 70 1-7 13.

Alberman, E. D. (1977) ‘Sociobiologic factors and birth weight in Great Britain.’ In Reed, D. M., Stanley, F. J. (Eds.) The Epidemiology of Prematurity. Baltimore: Urban & Schwartzenberg.

Lee, K-S., Paneth, N., Gartner, L. M.. Pearlman, M. A., Gruss. L. (1980) ‘Neonatal mortality: an analysis of the recent improvement in the United States.’ American Journal of Public Health. 70,

Cussen, G . H., Barry, J . E., Moloney, A. M., Buckley, N. M., Crowley. M.. Daly, C. (1978) ‘Cerebral palsy: a regional study.’ Irish Medical Journal, 71, 568-572.

Fryers, T., McKay, R. L. (1979) ‘The epidemiology of severe mental handicap.’ Ear& Human Development. 3, 277-294.

Susser. M. W., Kushlik. A. (1961) A Report on the Mental Health Services of the City of Salford ,for /he Year 1960. Salford: Salford Health Department.

Susser. M. W. (1968) Community Psychiatry: Epidemiologic and Social Themes. New York: Random House.

15-21.

PLASMA EXCHANGE IN ACUTE POST-INFECTIOUS

BETWEEN 1827 and 1836;Paris hospitals alone used five to six million leeches annually to suck 1,680,000 litres of blood from French people in order ‘to suck all deleterious matter from the body”. There were certain to be successes; a parallel example is that improvement now is seen in as many as 60 per cent of multiple sclerosis sufferers receiving placebo therapy. Comparison may be drawn between the motives for leeching and its modern-day successor, plasma exchange (PE), of which there are now many reports claiming success in

538

DEMYELINATION

ANNOTATIONS

many conditions, including peripheral and central nervous system demyelination. In this annotation the rationale for PE will be reviewed and the method’s current status assessed.

The method Plasma exchange involves the principle of removing whole blood from the patient and

separating cells from plasma by means of centrifugation. The patient’s cells are then returned along with replacement fluid, and the plasma is discarded.

A number of machines are available which incorporate either a continuous or semi- continuous flow type of cell separator. The latter has a disposable system and tends to be cheaper and more mobile. Of the two replacement fluids principally used, purified protein fraction (PPF) is preferred to fresh frozen plasma (FFP), as it is more readily available and cheaper, and because it is globulin free it will not fuel a continuing immunopathological process by replenishing complement levels. The removal of the globulin fraction by PE and its replacement by PPF seems to have no practical deleterious consequences.

Technical aspects and the use of PE in a variety of diseases has been well reviewed by PINCHING~. Myasthenia gravis, a disease of abnormal antibody production, and the vasculitides, including systemic lupus erythematosis, a disease due to circulating immune complexes, are of principal interest to neurologists.

Procedural difficulties in children centre on- access to the circulation and the circulation volume sequestered in the machine during PE. The recent availability of a 125ml centrifugation bowl has widened the scope, allowing children of lOkg or so to receive exchange. Radial artery or femoral vein cannulation usually provides an adequate flow-rate. Calcium and potassium may be added to replacement fluid to avoid electrolyte imbalance, and infection has not proved to be a serious problem.

Post-infectious demyelination and the rationale for plasma exchange The nature of an invading virus, its mode of entry into the nervous system, the host’s

histocompatability and immune status, metabolic upsets influencing membrane permeability and the concentration of antigenic determinants are all important in the production of demyelination’ and in determining its site.

Following replication in host cells, viruses may produce circulatory antigens by ‘revealing’ encephalitogenic or neuritogenic myelin basic protein or, by means of hapten formation, normal cell constituents such as lecithin or sulfatide may become antigenic4. These may induce autolysis if they become attached to host cells or combine with complement, antibody or other serum factors. Circulating immune complexes may become preferentially adherent to cerebral capillaries or the fenestrated endothelium of the choroid plexus. Perivascular inflammation with focal demyelination may thus result. Other organisms, drugs and vaccinations may fuel the same immune process’. A spectrum of involvement varying from encephalitis to transverse myelitis to polyradiculitis to peripheral neuritis is seen. These clinical entities often overlap; encephalomyelitis is very common and demyelination in the proximal segments of peripheral nerves is seen in multiple sclerosis, and antigen typical for CNS myeline has been isolated from these segments4.

The division of parainfectious encephalopathic illnesses into those resulting from direct invasion of a virus and those resulting from autoallergic processes therefore is probably illogical, as in most such illnesses both factors may be contributory. The histological appearance of these entities forms the basis of their classification. Acute haemorrhagic leucoencephalitis is probably a n hyperacute form of acute disseminated

539

ANNOTATIONS

encephalomyelitis-complement activation playing a greater rble-and the clinical course reflects the underlying pathology to some extent. They are probably part of the spectrum of the same diverse process, with the chronic remitting and relapsing demyelination of multiple sclerosis lying at the other end of the same spectrum. Subacute sclerosing panencephalitis might also be included. Immunological evidence from patients with these disorders, along with evidence from experimental allergic encephalomyelitis, forms the basis of our understanding of these conditions. Similar immunopathological mechanisms determine the peripheral nervous system demyelination of the Landry, Guillain-BarrC and Strohl (LGBS) syndrome, and its experimental equivalent, experimental allergic neuritis.

However, it remains difficult to discern which immunological reactions are a direct consequence of the primary host response and which are secondary undesirable effects. Further evaluation of this may allow some rationalisation of treatment.

Cell-mediated immunity plays a central rble in these demyelinating conditions. Cell- mediated immunity to myelin-basic encephalitogenic protein6* ' has been demonstrated but it seems the immune reaction need not necessarily be directed to myelin itselfs. Disordered humoral immunity is also evident and complement-fixing antibody has been found in patients with acute disseminated encephalomyelitis', as well as in patients with experimental allergic encephalo-myelitis''. In addition, a serum factor capable of demyelinating nervous tissue in tissue culture has been found in acute disseminated encephalomyelitis I I .

Autoantibodies against myelin12* 1 3 , the oligodendroglia and other brain components14' '' have been demonstrated in multiple sclerosis, and 'blocking factors' present in sera slow nerve conduction in vitro16. IgG and complement are preferentially localised to the peripheral zone of active demyelination in plaques'' and the antibodies are produced within the central nervous system.

Disordered cell-mediated and humoral immunity are also seen in the LGBS syndrome. Cellular hypersensitivity to PZ protein, a neuritogenic constituent in peripheral nerves, has been demonstrated" and demyelination has been shown to be secondary to the penetration of the Schwann-cell cytoplasm by the processes of mononuclear cells'9. However, this disordered cellular immunity with abnormal T-cell subpopulations seems to be dependent on circulating immune complexes2' and other humoral component^^'-^^. Serum from animals with experimental allergic neuritis can cause demeylination of peripheral nerves in ~ i t r o ~ ~ ; similarly, serum from patients with LGBS syndrome is toxic to peripheral myelin in tissue culture2'.

Plasma exchange may exert its beneficial effect in demyelinating diseases by the removal of autoantibodies, neuroelectric blocking factors and significant subpopulations of lymphocytes, along with humoral components on which the cell-mediated response is reliant. Even tissue-bound immune complexes may be removed25, and CSF immunoglobulin levels have been shown to be reduced following PEZ6.

The potential for repair of the peripheral nervous system is well known and the capacity of repair, and particularly remyelination, in the central nervous system has been reviewed elsewhere", ". Much evidence is drawn from post-traumatic cases, but similar mechanisms probably apply in the conditions under discussion.

Plasma exchange and demyelination-current status and chronic

p o l y n e u r o p a t h i e ~ ~ ~ - ~ ~ , including the Miller-Fisher variant". Oral steroids possibly do no 540

There are now many reports of benefit from using PE in

ANNOTATIONS

good and may do harm, though the intravenous route may offer some benefit34-36. Of 16 acute cases presented to the American Academy of Neurology last year, 12 improved and four did not. These preliminary anecdotal reports should now be followed by careful evaluation of the method by means of prospective trials. However, because the incidence is only 1.2 cases per 100,000 population per year3’, a multicentre approach is mandatory. Such a trial is now in progress in the United States and Canada3’. Ventilatory failure occurring in about 25 per cent of cases is the main threat to life, and these cases should be offered the possible benefit of PE. Ventilatory function may be monitored accurately by spirometry, allowing the course of the illness and rate of recovery to be recorded and measured.

In addition to the LGBS syndrome, we have had recent success in Manchester in the use of using PE in a case of acute disseminated encephalomyelitis and of transverse myelitis. A 12- year-old girl with acute post-infectious encephalopathy was in a chronic vegetative state, with non-reactive pupils, for several weeks until PE was performed. Within two weeks of three exchanges she had regained consciousness, her spastic quadriparesis was resolving and her VERS were showing progressive improvement. Recovery has continued since and it is hoped that she will return to school with only a mild handicap. A two-year-old boy with transverse myelitis and quadriparesis required ventilatory support for five months. Within three weeks of two exchanges he was breathing on his own and limb function is returning slowly.* Evaluation of these patients is far more difficult, as their parameters of recovery do not lend themselves so well to quantitative analysis as do those of patients with LGBS syndrome.

Largely uncontrolled series suggest that steroids are of some benefit in some cases of acute disseminated encephalomyelitis and transverse myelitis, and antiviral agents are currently being assessed3*. Reduction of raised intracranial pressure is essential. Preliminary reports are available on the use of PE in multiple sclerosis26. 39, but not in acute demyelinating illness in childhood. However, with a mortality rate of 20 per cent in some series of acute post- infectious encephalopathy, and a morbidity rate of 30 per cent, PEshould be evaluated, and again by means of prospective trials with controls. Coma or respiratory failure usually herald the greatest risk of poor outcome and it is these patients who should be offered the possible benefits. The protocol should allow evaluation to be made independently of steroids or antiviral agents used.

In all cases, immunological study of the patient’s plasma removed at exchange may allow better understanding of the illness. *Detailed case histories availabie from author on request.

RICHARD NEWTON EEG Department, Booth Hall Children’s Hospital, Charlestown Road, Blackley, Manchester M9 2AA.

REFERENCES I . Glasscheib, H. S. (1963) The March qf Medicine. London: MacDonald. 2. Pinching, A. J . (1980) In: Thompson, C . A. (Ed.) Receni Advances in Clinical Immunology.

3. Legg, N. (1975) ‘How viruses affect the central nervous system.’ In: Williams, D. (Ed.) Modern

54 1

Edinburgh: Churchill Livingstone.

Trends in Neuroioe,.. 6 , London: Butterworth

DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 198 1,23

4. Ryberg, B. (1979) 'Multiple specificities of antibrain antibodies in multiple sclerosis and chronic myelopathy.' Journal of the Neurological Sciences, 38, 357-382.

5. Behan, P. O., Currie, S. (1978) Clinical Neuroimmunology. London: Saunders. Ch. 3.4.6. 6. Behan. P. 0.. Geschwind, N.. Lamarche, J . B., Lisak. R. P., Kies, M. W. (1968) 'Delayed

hypersensitivity to encephalitogenic protein in disseminated encephalomyelitis.' Lancer. 2 , 1 009- 1 0 I 2.

7. Lisak. R. P.. Behan, P. O., Zweiman, B., Shetty, T. (1974) 'Cell-mediated immunity to myelin basic protein in acute disseminated encephalomyelitis.' Neurology. 24, 560-564.

8. Wisniewski, H. M., Bloom, B. R. (1975) 'Primary demyelination asa non-specificconsequenceofa cell- mediated immune reaction.' Journal of Experimenral Medicine. 141, 346-359.

9. Appelbaum. E., Greenberg, M., Nelson, J . ( 1953) 'Neurological complications following anti- rabies vaccination.' Journal of the American Medical Associarion. 151, 188- 191.

10. Paterson, P. Y., Coia. E. M., Jacobs, A. F. (1965) 'Complement-fixing antibrain antibodies and allergic encephalomyelitis. I: Characterization of the antibodies.' Annals of rhe New York Academy of Sciences. 122. 256-265.

1 1 . Bornstein. M. B., Raine, C. S. (1976) 'Central nervous system.' In: Miescher. P. A., Muller- Eberhard, H. J. (Eds.) Clinical Immunopathology. New York: Grune & Stratton. Vol. 11, Ch. 40.

12. Panitch, H. S., Haslar, D. A.. Johnson, K. P. (1978) 'Antibodies to myelin basic protein in multiple sclerosis: clinical correlations.' Neurology. 28, 394.

13. Lisak, R. P., Zweiman, B., Norman, M. (1975) 'Antimyelin antibodies in neurological diseases.' Archives of Neurolo,yy. 32, 163-167.

14. Abramsky, 0.. Lisak. R. P., Silberberg. D. H., Pleasure, D. E. (1977)'Antibodies to oligodendroglia in patients with multiple sclerosis.' New England Journal of Medicine. 297, 1207-121 I .

15. Laurell, A. B., Link, I. ( 1972) 'Complement-fixing antibodies in multiple sclerosis.' Aria Neurologica Scandinavica. 48, 46 1-466.

16. Schauf, C. L., Schauf, V.. Davis, F. A., Mizen, R. (1978) 'Complement-dependent serum: neuroelectric blocking activity in multiple sclerosis.' Neurology, 28, 426-430.

17. Lumsden, C. D. (1971) 'The immunogenesis of the multiple sclerosis plaque.' Brain Research. 28,

18. Sheremata, Y., Colby. S . , Karkhonis, Y., Eyler, E. H. (1975) 'Cellular hypersensitivity to basic myelin (P2) protein in the Guillain Barrk syndrome.' Canadian Journal of Neurolo,?ica/ Science. 2 , 87-90.

19. Vital, C., Bonnaud, E., Vallat, J. M.. Coquet, M., Rival. J., Bioulac, P.. Brachenmacher. C. (1978) 'Etude ultrastructurale du nerf pkriphirique.' Archives d'Anatomie er (Ie Cytolo,yie Parhologiques.

20. Goust, J . M., Chenais, F., Carnes, J . E.. Hames, C. G.. Fudenberg, H. H., Hogan, E. L. (1978) 'Abnormal T cell sub-populations and circulating immune complexes in the Guillain BarrC syndrome and multiple sclerosis.' Neurology. 28, 421-425.

21. Cook, C. D., Dowling. P. C., Murray, M. R., Whitaker, J . N. (1971) 'Circulating demyelinating factors in acute idiopathic polyneuropathy.' Archives of Neurolo.?v. 24, 136-144.

22. Luijten, J. A., Baart de la Faille-Kuyp, E. H. (1972) 'The occurrence of IgM and complement factors along myelin sheaths of peripheral nerves. An immunohistochemical study of the Guillain Bard syndrome.' Journal of the Neurological Sciences. 15, 2 19-224.

23. Cook, S.. Murray, M. R., Whitaker, J . N.. Dowling, P. (1969) 'Myelinotoxic antibody in the Guillain Barrk syndrome.' Neurology, 19, 284.

24. Yonezawa, T., Ishihara, Y., Matsuyama, H. (1968) 'Studies on experimental allergic peripheral neuritis. I: Demyelinating patterns studied in vitro. ' Journal of Neuropatholo,yr and E.rperimenta/ Neurolqyy. 21, 453-463.

25. Hamilton, W. A. P., Vergani. D.. Bevis. L., Tee, D. E. H.. Zilkha, K . J.. Cotton. L. T. (1980) 'Plasma exchange in SLE.' Lancer. 1. 1249.

26. Weiner. H. L.. Dawson, D. M. (1980) 'Plasmapheresis in multiple sclerosis. Preliminary study.' Neurology, 30, 1029-1033.

27. Berry, M. (1979)'Regeneration in the central nervous system.' In: Smith, W. T.. Cavanagh, J . B. (Eds.) Recent Advances in Neuroparholo,q~. Edinburgh: Churchill Livingstone.

28. Brettle. R. P.. Gross, M., Legg. N. J., Lockwood, M.. Pallis. C. (1978) 'Treatment of acute polyneuropathy by plasma exchange.' Lancet, 2. 1100.

29. Fowler, H., Vulpe, M., Marks, G., Egolf. C., Dau, P. C. (1979) *Recovery from chronic progressive polyneuropathy after treatment with plasma exchange and cyclophosphamide.' Lancer. 2, I 193.

30. Asbury, A., Fisher, R.. McKhann. G . . Mobley, W.. Server, A. (1980)'Guillain Barrisyndrome. Is there a role for plasmapheresis?' Neurology. 30. I I 12.

31. Levy, R. L.. Newkirk, R., Ochoa, J . (1979) 'Treating chronic relapsing Guillain BarrC syndrome by plasma exchange.' Lancer. 2 , 259-260.

32. Toyka, K. V., Augspach, R.. Paulaus. W., Grabensee, B.. Hein. D. (1980) 'Plasma exchange in polyradiculopathy.' Annals of Neurologj~. 8. 205-206.

33. Littlewood, R.. Bajada, S. (1981) 'Successful plasmapheresis in the Miller Fisher syndrome.' British Medical Journal. 282, 778.

365-390.

26, 276-282.

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ANNOTATIONS

34. Hughes, R. A.. Newsom-Davis, J. M., Perkin, G. D., Pierce, J. M. (1978) ‘Controlled trial of prednisolone in acute polyneuropathy.’ Lance/. 2, 750-753.

35. Dowling, P. C., Bosch. V. V., Cook, S. D. (1980) ‘Possible beneficial effect of high dose intravenous steroid therapy in acute demyelinating disease and transverse myelitis.’ Neurology,

36. Brumback, R. A. (1980) ‘Failure of oral versus parenteral cortico-steroids in a case of acute inflammatory polyradiculoneuropathy (Guillain Barre syndrome).’ Australia and New Zealand Journal of Medicine, 10, 224-226.

37. Shoenberg. B. S. (1978) ‘Epidemiology of Guillain BarrC syndrome.’ Advances in Neurology.

38. Ross, E. M., Bellman, M. H. (1979) ‘Encephalitis and encephalopathy.’ In: Rose, F. C. (Ed.)

39. Da, P. C.. Petajan, J. H., Johnson, K. P., Panitch, H. S., Bornstein, M. B. (1980) ‘Plasmapheresis

30, 33-36.

19, 249-260.

Paediarric Neurology. Oxford: Blackwell.

in multiple sclerosis: preliminary findings.’ Neuro1o.q.v. 30, 1023-1028.

Notices

Margaret Lowenfeld Memorial Seminar Cambridge, 9th October 1981

DR Catherine Urwin, Lecturer in Psychology, University of Warwick (Lowenfeld Memorial Fellow elect) will lecture on ‘Communication and Protolanguage’ in the Small Lecture Room, Medical Education Building, New Addenbrooke’s Hospital, Hills Road, Cambridge, on Friday 9th October 1981 at 5pm.

Fifth Symposium on Cerebral Palsy and Other Motor Disorders Antwerp, 13th-14th November 1981

THE above symposium will be held under the auspices of the Belgian Association for Child Neurology, the Belgian Seminars for Rehabilitation and the Flemish Paediatric Association. On November 13th the general theme will be ‘Testing and Rehabilitation Techniques’ (language Dutch; rksumts in English) and on November 14th the subjects will be medical and neurophysiological (languages Dutch, French and German; rtsumts in English). Further details from Dr. H. Jansseune, Medisch-Pedagogisch Instituut Sint-Jozef, Galjoenstraat 2, 2030 Antwerp, Belgium.

Teaching the Learningdisabled Child New York, 15rh-18th November 1981

TtrE New York Branch of The Orton Society will hold its Fall Institute in Monticello, New York, from 15th to 18th November 1981. The theme will be‘] low the learning-disabledchild can learn: focus on teaching and learning’. Topics will include the problems of spelling, the social roots of language disability, writing skills for the dyslexic adolescent and survival techniques for the learning-disabled adolescent. Further details from New York Branch of the Orton Society, Inc., 80 Fifth Avenue, New York, N.Y. 1001 1. Tel.: (212) 691-1930.

543