IMPORTANCE OF ANATOMICAL FEATURES IN UNRAVELLING MECHANISMS OF DEMYELINATION

1214 there was no logical reason to suppose that this was so, he was put under surveillance by the Workers’ Compensation Insurance carrier, and moving pictures were taken of him working hard pruning trees. He used his right and left arms interchangeably for long periods, raised both arms above his head to cut branches, and stuffed the clippings into a bin and tamped them down vigorously, using his right arm. In retrospect, it would have been better to have decided early on to leave the pellet alone, to have reassured the patient authoritatively that the pellet was near no vital structures and would cause him no more symptoms, and to have encouraged his return to work. Neurology Associates, Chevy Chase, Maryland 20815, USA

RAMON B.

JENKINS

MEASUREMENT OF GASTRIC EMPTYING RATES

SIR,-There are drawbacks to the impedance method of measuring gastric emptying described by Dr Sutton and colleagues (April 20, p 898). First, the method cannot be used to study the emptying of solid food and may not be amenable to the evaluation of the emptying of liquids of varied and higher caloric composition. Secondly, changes in impedance in the region illustrated may merely reflect transfer of liquid from proximal to distal stomach and do not necessarily measure gastric emptying. Thirdly, electrical stimulation of the abdominal dermatomes elicits somatovisceral reflexes 1,2 that alter gastric contractility and may therefore influence gastric emptying (see the declination curve and gastric emptying parameters of volunteer 1 in top left hand panel of Sutton and colleagues’ fig 3). Why was the impedance method compared with single scanner scintigraphic gastric emptying? Any new method should be evaluated against the best available one and should be applicable to the study of conditions that are most relevant in health and disease. In the assessment of gastric emptying, the evaluation of solid phase emptying is essential. Although a cheaper, efficient method of measuring gastric emptying is needed, the impedance method proposed falls short of expectations in accuracy and applicability and may interfere with the biological response under investigation. Gastroenterology Unit, Mayo Medical School, Saint Marys Hospital, Rochester, Minnesota 55901, USA

MICHAEL CAMILLERI

A, Schmidt RF. Somatosympathetic reflexes: Afferent fibers, central pathways, discharge characteristics. Physiol Rev 1973; 53: 916-47. 2. Camilleri M, Malagelada J-R, Kao PC, Zinsmeister AR. Effect of somatovisceral reflexes and selective dermatomal stimulation on postcibal antral pressure activity. Am J Physiol 1984; 247: G703-G708. 1. Sato

SIR,-For the measurement of gastric emptying I agree that electrical methods have distinct advantages and endorse Dr Sutton and colleagues’ criticism of other methods. Much pioneer work has been done with the four electrode system but the electrodes need to be accurately placed in both the vertical and horizontal planes to ensure that the electric current passes through the stomach. Might there not be difficulties or potential errors with this system in the elderly, the obese, or the postoperative patient, particularly since the method of electrode placement does not rely on fixed anatomical

points?

’

In the University of Sheffield departments of surgery and medical physics, we are developing and validating applied potential tomography (APT) for the measurement of gastric emptying. This method produces an image of resistivity changes by means of a ring of sixteen electrodes placed around the epigastrium at the level of the 8th costal cartilage. The electrodes will record changes within an 8 cm "slice" of the torso. This increases the collecting area in the vertical plane and, since the electrodes are in a complete ring, there is no error in the horizontal plane. In ten volunteers we found good overall correlation between the emptying curves as measured simultaneously by APT and radioisotope scanning (r=0-91) and no significant difference between the half emptying times (p>0 05). We showed, by marking

the electrodes with a cobalt-57 "pencil", that they passed through the level of the mid-body of the stomach on every occasion. Our results therefore accord with those of Sutton et al in showing that electrical methods are valid and, because they are completely noninvasive, worthy of further study. University Surgical Unit, Royal Hallamshire Hospital,

R. AVILL

Sheffield S10 2JF

AGEING IN DOWN’S SYNDROME

SIR,-Your April 13 editorial builds a very elaborate hypothesis about ageing, based on Down’s syndrome as a model. However, there is no evidence that premature ageing is a feature of the syndrome. The evidence cited in your editorial refers mainly to the increased prevalence of autoimmune disease and Alzheimer’s degeneration in Down’s syndrome adults, but there is other evidence, not cited, which suggests the opposite. A controlled in vitro study of limit strain in samples of fullthickness skin from five patients with Down’s syndrome aged 37-62 showed no evidence of premature ageing.l Furthermore, another study in Down’s adultsshowed no age-related rise in blood pressure, cholesterol, or triglycerides and found no evidence of atheroma. The thyroid autoimmune disease in Down’s syndrome is not age related3 and I have seen children aged eight with autoimmune thyroiditis. Certainly adults with Down’s syndrome develop Alzheimer’s degeneration but is there really any evidence that this pathological state is age related? Department of General Practice, Medical School, University of Otago,

J. C. MURDOCH

Dunedin, New Zealand

Murdoch JC, Evans JH. An objective invitro study of ageing in the skin of patients with Down’s syndrome. J Ment Defic Res 1978; 22: 131-35. 2. Murdoch JC, Rodger JC, Rao SS, Fletcher CD, Dunnigan MG. Down’s syndrome: an atheroma free model? Br Med J 1977; ii: 226-28. 3. Murdoch JC, Ratcliffe WA, McLarty DG, Rodger JC, Ratcliffe JG. Thyroid function in adults with Down’s syndrome. J Clin Endocrinol Metab 1977; 44: 453-58. 1.

IMPORTANCE OF ANATOMICAL FEATURES IN UNRAVELLING MECHANISMS OF DEMYELINATION

SIR,-The comprehensive editorial on this subject (March 2, p 495) epitomises the many recent advances in this area and gives rise to hopes that the aetiology of multiple sclerosis (MS) may soon be known. However, necropsy specimens of early lesions, which probably hold the key to understanding of this disorder, are hard to come by. Standard methods of fixation and post-mortem changes may produce artefacts or destroy important evidence. It is very doubtful if the very early changes have been examined adequately, because of the shortage of material. Such a difficulty arises even in animal models, such as chronic relapsing experimental allergic encephalitis (EAE), where demyelination occurs only after the first relapse, thus making it difficult to synchronise the sampling with the earliest stage of the

demyelination. Studies of an acute form of demyelinating EAE in guineapigsl,2 and in Lewis ratsj seem to be throwing light on the changes in MS. The method entails sensitising animals to a foreign protein as a of provoking demyelination by the administration of myelin basic protein and adjuvant. The pattern of demyelination, which is often very extensive, resembles that in MS and indicates that certain neuroanatomical features in the central nervous system, both in the experimental situation and the human disease, tend to determine the sites of the lesions. Their actual topography may turn out to be of fundamental importance in understanding the disease process. Some of these topographical features have been mentioned in early of MS and even illustrated in the first publications on the description of MS. Not enough attention is being paid to them. The important anatomical features are as follows: 1. The undue vulnerability of the posterior columns in the spinal cord, responsible for the loss of vibration sense and L’hermitte’s sign (the electric sign). means

pathology

.

1215

tendency to subpial demyelination of the spinal cord, forming either a narrow ribbon or wedge in transverse section; the base of the wedge lies on the surface of the cord.

late) 1950s has a similar record, on the basis of which the Central Laboratory of the Swiss Red Cross has obtained FDA licences for its albumin and IVIG; so far, over 1500 kg of the.IVIG

3. The perivascular distribution of demyelination, in relation to the veins and venules. 4. The tendency to the formation of "dumb-bell" lesions when two venules occur in close proximity. 5. The formation of lesions on either side of a cleft-ie, the so-called "kissing" lesions in the cord or cerebrum. 6. The periventricular distribution of lesions. 7. The undue vulnerability of the optic nerves. 8. The special type of MS lesion in Balo’s disease where certain zones (which are almost certainly related to the anatomy of the vessels) escape demyelination, to leave a concentric appearance in some sections. 9. The symmetry of affected areas, particularly in the spinal cord. All these indicate that at the sites of the lesions there are very important local features which contribute to the process of demyelination in MS. The unravelling of the mechanisms of autoimmune demyelination in the CNS may provide important clues about the similar processes in other organs which are less easy to examine histologically and perhaps to understanding the "degenerative" diseases of the nervous system.

has been used in clinics all over the world, sometimes in a very high dosage; no instance of transmission of any infectious disease has been reported. Despite the safety record of IgG prepared by the cold-ethanol methods, isolated cases of transmission of hepatitis B have been recorded.7,8 One incident was investigated in great detail;8 the material had been prepared by an American manufacturer and according to methods 6 and 9 of Cohn4and transmission of hepatitis to chimpanzees was proved. No such case is known for the K/N method. Transmission of non-A, non-B hepatitis has been reported for two experimental lots of IVIG-one prepared in the UK by K/N fractionation,3,9 isolation being followed by a treatment to make the product suitable for intravenous administration; the other, prepared by an American manufacturerlO starting from Cohn fraction 11,4,5 was a newly developed preparation for intravenous application that was being tested clinically. The reasons for the infectivity observed are unclear in both cases and the observations are in striking contrast with

2. The

‘

I thank Prof Dudley C. Dumonde for help and encouragement; Dr Marian Kies of the National Institutes of Health for gifts of myelin basic protein; Mr Terence J. Bartlett for technical assistance; and Action for Research into Multiple Sclerosis (ARMS) for their support.

Rayne Institute, St Thomas’ Hospital, London SE1 7EH

JACK COLOVER

1. Colover J. A new pattern of

spinal-cord demyelination in guinea pigs with experimental allergic encephalomyelitis mimicking multiple sclerosis. Br J Exp Pathol 1980; 61:

(’Sandoglobulin’)

Oncley

previous experience. Experience so far has demonstrated the extraordinary safety of both the Cohn4,5 and KlN1,2 processes; however, complete absence of infectious agents cannot be guaranteed for either method. It is therefore still imperative to use raw material obtained from a segment of the population which does not carry an increased risk of transmitting infectious diseases. Central Laboratory, Swiss Red Cross Blood Transfusion Service, CH-3000 Bern 22, Switzerland

H. FRIEDLI

J.-J. MORGENTHALER

390-400.

J Acute demyelination in EAE after pretreatment with foreign protein and muramyl dipeptide (MDP). In: Alvord EA Jr, Kies MW, Suckling AJ, eds. Experimental allergic encephalomyelitis: A useful model for multiple sclerosis.

2. Colover

New York: Alan R. Liss, 1984: 37-42. 3. Colover J. Distinctive spinal cord lesions in EAE in animals pretreated with ovalbumin and myramyl dipeptide. In: Huber A, Klein D, eds. Neurogenetics and neuroophthalmology. Amsterdam: Elsevier/North Holland, 1981: 103-06. 4 Cruveilhier J. Anatomie pathologique du corps humaine (32e livre). Paris: Baillière, 1835-42: 22.

KISTLER/NITSCHMANN PLASMA FRACTIONATION METHODS

SIR,-Dr Hein and others(Feb 16, p 405) try to cast doubts on the plasma fractionation method of Kistler and Nitschmann (K/N process)I,2; their comments are based on the transmission ofnon-A, non-B hepatitis by an experimental intravenous immunoglobulin (IVIG) preparation obtained by this fractionation method.3 Their remarks are, however, both erroneous and misleading. Although ionic strength has, in the KIN process (and in the Cohn process), a critical influence on the purity of the IgG, it is incorrect to infer that the K/N process is "less controlled"; a careful dosage of us to obtain consistently reproducible results. The "higher quality and purity" of the IgG obtained by Cohn’s methods 64and 95 compared with the IgG prepared by the K/N method, amounts to a difference in purity of 98 and 97%, respectively. It is surprising that Hein and others mention the method of Hink et al6 as one of the modifications of Cohn’s methods which is used in the United States, since this represents a much more drastic departure from Cohn’s original conditions than the K/N method does. Albumin prepared by Hink’s method has a purity of 85-90%, as compared with 97-99% for both Cohn and K/N albuminn. Readers not familiar with the methodology may get the impression from Hein and colleagues’ letter that the K/N procedure is inherently less safe than the Cohn method, and possibly that the K/N process is related to the unsafe Cohn method 12-and that these are reasons why the US Food and Drug Administration should not license products made by the K/N process. There is nothing magic about the Cohn method; the assumption that Cohn fractionation products are safe, rests entirely on their long-standing record. The KIN method, which was developed in the early (not

the

buffer

systems used allows

1. Nitschmann

H, Kistler P, Lergier W. Vereinfachtes Verfahren

humanem Albumin und

gamm-Globulin

aus

Blutplasma

zur

mittels

Gewinnung von Alkoholfällung.

Helv Chim Acta 1954; 37: 866-73.

Large scale production of human plasma fractions. Vox Sang 1962; 7: 414-24. 3. Lever AML, Webster ADB, Brown D, Thomas HC. Non-A, non-B hepatitis after intravenous gammaglobulin. Lancet 1985; i: 587. 4. Cohn EJ, Strong LE, Hughes WL, et al. Preparation and properties of serum and plasma proteins. J Am Chem Soc 1946; 68: 459-75. 5. Oncley JL, Melin M, Richert DS, et al The separation of antibodies, isoagglutinins, prothrombin, plasminogen, and beta-1-lipoprotein into subfractions of human plasma. J Am Chem Soc 1949; 71: 541-50. 6. Hink JH, Hidalgo J, Seeberg VP, Johnson FF. Preparation and properties of a heattreated human plasma protein fraction. Vox Sang 1957; 2: 174-86. 7. John TJ, Ninan GT, Rajagopalan MS, et al. Epidemic hepatitis B caused by commercial human immunoglobulin. Lancet 1979; i: 1074. 8. Tabor E, Gerety R. Transmission of hepatitis B by immune serum globulin. Lancer 1979; ii: 1293. 9. Lane RS Non-A, non-B hepatitis from intravenous immunoglobulin. Lancet 1983; ii: 2. Kistler P, Nitschmann H.

974-75. 10. Ochs HD, Fischer

SH, Virant FS, et al Non-A, non-B hepatitis immunoglobulin. Lancet 1985; i: 404-05.

and intravenous

ANTIBODIES TO HEPATITIS A AND B VIRUS ANTIGENS IN Rho (D) IMMUNE GLOBULIN

SIR,-We would like to comment on the article by Dr Tabor and colleagues (Jan 5, p 46). We tested 23 lots of Rho (D) immune globulin (RhIG) for antibodies to the antigens of hepatitis A and B viruses (HAV, HBV). These lots were released in 1983/84 by the Paul Ehrlich Institute, the Federal Government’s agency for sera and vaccines in the Federal Republic of Germany, and they originated from six different manufacturers (7, 4, 4, 3, 3, 2). Abbott radioimmunoassays were used to test for hepatitis antibodies. AntiHBs and anti-HAV were compared with the international reference preparations from the WHO. Anti-HBe and anti-HBc were compared also with a national reference preparation. All RhIG lots contained anti-HBs, anti-HBc, and anti-HAV. 16 lots contained anti-HBe. The antibody profile (see table) of RhIG was not identical to that reported by Tabor and colleagues. The antibody concentration was scattered over a wider range, except for anti-HBe. These findings 2 were identical to those found in immune serum globulin (IgG).1>2 100 IU per ampoule of the international reference preparation of