1310

OPV remains the bedrock of most controlprogrammes for poliomyelitis in developed countries.When intensive public health programmes are

mounted-as, for example, in Malaysia or Brazil-itcan be successful in developing countries too, but itdoes need an intensive effort and outbreaks of diseasecan occur, as illustrated by that in Taiwan. A greatdrawback is the heat lability and short shelf-life ofOPV, requiring a well-developed cold chain. Killedpoliovaccine, either alone or in combination with

living vaccine, is now being investigated for the controlof poliomyelitis in several countries.3,4 In a third paperin this issue (p 1317) Dr Darrell Salk and his colleaguesput forward a reasoned case for the use of one or twodoses of killed poliovaccine to provide immunologicalmemory. A single dose of potent vaccine at six monthsof age is sufficient to produce antibodies and stimulateimmunological memory as are two doses starting at twomonths. It is expected that a single dose of killedpoliovaccine at two months, or perhaps at birth, willinduce immunological memory. Thus, there are goodprospects of an alternative strategy for preventingpoliomyelitis to that afforded by OPV. A two-doseschedule of killed poliovaccine combined with

diphtheria and tetanus starting at two months or lesswould be very convenient and likely to be successful.We have previously argued that a combined

diphtheria-pertussis-tetanus (DPT)/polio vaccine ismore likely to achieve high coverage than OPV pluskilled DPT. There are two objections to this

strategy-anxieties about the pertussis element and thehigh cost of injected poliovaccine. The cost of injectedpoliovaccine can be reduced by the use of continuouscell lines such as Vero on microcarrier cultures; also thecosts of administration are substantially lessened byuse of a combined vaccine. This policy option needs tobe explored along the lines advocated by Salk et al. It isimportant to build confidence in a new programmestep by step. The recent withdrawal of batches ofpoliovaccine in the US and Canada because they hadlost potency shows how important it is to validate everystep in a new programme.9 The vaccine made in theNetherlands and described by Salk et al has provedstable, safe, and effective over several years and shouldform the basis for extended studies of the new policyoption. Meanwhile, the work described by Almond etaF offers a very exciting prospect for the future

development of vaccines. The understanding ofvirulence and attenuation of polioviruses at themolecular level is proceeding fast. So far, surprisinglyfew differences have emerged between attenuated andvirulent type 3 polioviruses, which bodes well for ourunderstanding of the mechanism and underlines thedeficiencies of the type 3 vaccine strain compared withtype 1. Such work could lead to better attenuated andkilled vaccines in future, but this prospect should notimpede the use of the tools we have at present whichhave so successfully controlled the disease.

9. Wall Street Journal, Nov 8, 1984.

Vascular Disease, Senility, andDementia

ABOUT 1 o’clock in the afternoon of July 25, 1694,and after suffering from palpitations and pissing ofblood for many years, the great anatomist and

physician to the Pope, Dr Malpighi, was seized withapoplexy with a palsy of the whole right side anddistortion of the mouth and right eye. Despitebleeding, cupping, and application of the powder ofCornachini and Sinapismus to the soles of his feet herecovered from the palsy after 40 days but was leftsomewhat demented, impaired in memory and reasonwith emotional weakness, melting into tears upon theslightest occasion, with intervals of inappetency andslight fits of giddiness. On Nov 29 that year he had afurther apoplectic fit and died. A week later, GeorgeBaglivi dissected his corpse. The heart was larger thanordinary and there were about 2 pints of black clottedblood in the brain. The blood vessels of the brain weredilated and broke on all hands.2Alzheimer, in 1906 and 1907, distinguished a

specific kind of dementia, named after him by Kraepelinand first thought of as a presenile psychosis in whichsigns of arteriosclerotic change in the brain were

distinctly rare.3,4 The brain was diffusely shrunken,sometimes with a thickened pia-arachnoid, and withtwo virtually constant histopathological changes-senile plaques and intracellular fibrillary lesions.Patients with Alzheimer’s disease had symptoms of anenfeebled mind, confusion, restlessness, excitement, orhallucinosis rather than the sudden stroke and focal

signs of Dr Malpighi. One peculiarity of Alzheimer’sdisease is its onset before old age is imagined to begin,but nearly all examples can be grouped with other casesof senile dementia in which there are senile plaques andneurofibrils. Old age itself is unlikely to be a diseaseand Critchley in 1930 found there were no "senile"plaques in the brain of two persons aged 101 and 103.5These two histological correlates of vascular and

parenchymal dementia are easily recognisable by,neuropathologists. The dementia of cerebralarteriosclerosis is probably due to multiple cerebralinfarctions6-s and is commonly referred to as multi-infarct dementia.9 This is sometimes associated withthe white matter degeneration and demyelination of

1. Major RH. The history of the sickness of Marcellus Malpighi, the Pope’s physician,with an account of the dissection of his corpse. In: Classic descriptions of diseaseSpringfield: Thomas, 1945. 476-77.

2. Baglivi G. The practice of physick. London: Bell, 1704 461.3. Alzheimer A. Über eigenartige Krankheitsfalle des spätern Alters. Z Neurol Psychiat

1911; 4: 356-85.4. Alzheimer A Uber eine eigenartige Erkrangung der Hirnrinde. Allg Z Psychiat 1907,

64: 146-48

5. Critchley M. The pathology of the senile psychoses. Proc Roy Soc Med 1930; 23:533-43.

6 Fisher CM. Dementia and cerebral vascular diseases. In. Toole JF, Siekert RG,Wishnant JP, eds. Cerebral vascular diseases (6th Princeton Conference). NewYork, 1968.

7. Worm-Peterson J, Pakkenberg H Atherosclerosis of cerebral arteries, pathological andclinical correlations. Acta Neurol Scand 1967; 43 (suppl 31).

8. Bousser MG. Les conceptions actuelles de démences artériopathiques. L’ Encéphale1977; 3: 357-72.

9 Hachinski VC, Lassen NA, Marshall J Multi-infarct dementia, a cause of mentaldeterioration in the elderly. Lancet 1974, ii: 207-10.

1311

Binswanger’s syndrome. The cause of Alzheimer’sdisease is unknown: Maudsley affirmed that the brainhad to be fed with energy from below if it was not towear out.

A small percentage of all cases of dementia are

due to other causes including normal pressure

hydrocephalus, cerebral syphilis, alcoholism, Pick’sdisease, and tumours; and depressive pseudodementiacan mimic the syndrome.’"’" Most of these can berecognised by specific tests. Since some of theseconditions are treatable, it is necessary to achieve an

early and specific diagnosis. Some 15-25% ofdemented patients show signs of both multi-infarctdementia and Alzheimer’s disease-a condition calledmixed dementia, 12-14 although this term is

unsatisfactory and two common conditions in theelderly must sometimes coexist.A neurological examination may separate multi-

infarct dementia and Alzheimer’s disease,15 but thereare few published studies and the clinician will often bewrong. Cerebral arteriosclerosis may be local or

generalised, slight or pronounced, and the earliestsigns and symptoms of vascular and parenchymaldementias may be similar with irritability, apathy, orapprehension as well as failing mental powers.However, focal neurological symptoms and signs,although occurring in both illnesses, are much morecommon in cerebrovascular disease. In Swedish

patients from Umea, Bucht and his colleagues]6foundfocal signs in 14 of 20 patients with vascular dementiabut in only 1 of 19 patients with the Alzheimer typeof illness: others have reported similarly." Wilsonl8judged that the arteriopath who was demented

preserved his insight longer than the senile dement,although epilepsy and motor signs were more common,the vascular process terminating in rigidity,paraplegia, incontinence, and status epilepticus. Oneof Wilson’s arteriopathic subjects had nine hundredleft facio-brachial fits in 48 hours. However, transientpareses, occasional fits, and rigidity also occur in

subjects with necropsy findings typical of Alzheimer’sdisease. Even more important than focal signs for thediagnosis of multi-infarct dementia is the punctatehistorical sequence of symptoms with a multitude ofstrokes on a background of intellectual decline. Age,sex, and family and psychiatric history are of less value

10. Freeman FR. Evaluation of patients with progressive intellectual deterioration. ArchNeurol 1976; 33: 658-59.

11. Victoratos GC, Lenman JAR, Herzberg L. Neurological investigation of dementia. BrJ Psychiatry 1977; 130: 131-33

12 Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented oldpeople J Neurol Sci 1970; 11: 205-42.

13 Hutton JT. Clinical nosology of the dementing illnesses. In: Maletta GJ, Pirozzolo FJ,eds Advances in neurogerontology New York: Praeger, 1980. 149.

14. Reisberg B, Ferris SH. Diagnosis and assessment of the older patient. Hosp CommunityPsychiatry 1982; 33: 104-10.

15 Scheinberg P Multi-infarct dementia. In: Katzman R, Terry RD, Bick KL, edsAging, vol 7 New York: Raven, 1978 105.

16. Bucht G, Adolfsson R, Winblad B Dementia of the Alzheimer type and multi-infarctdementia: A clinical description and diagnostic problems J Am Gertatr Soc 1984;32: 491-98.

17 Sluss TK, Gruenberg EM, Rabins P, Kramer M. Distribution of focal signs in a groupof demented men. Neuropsychobiology 1982; 8: 109-12.

15 Wilson SAK. Cerebral arteriosclerosis. In: Bruce AN, ed Neurology, 2nd ed. London-Butterworth, 1955. vol 3, 1407

in diagnosis. Bucht et al’6 found that a third of theirsubjects with brain infarcts had been depressed beforethe dementing illness started, whereas depression wasrare before the onset of Alzheimer’s disease. However,once the diseases were established, depression wasmore common in parenchymal than in vasculardementia.

In many instances, a cardiac examination will help todistinguish the possibility of multi-infarct dementiafrom Alzheimer’s disease. Most patients with vasculardementia, but only a minority of those with

parenchymal dementia, have a history ofcardiovascular disease (65% and 11%, respectively, inthe study of Bucht et al 16 ). Blood-pressure is high inarteriopaths (as we might expect), ’but is sometimessubnormal in subjects with Alzheimer’s disease.16,19 Inmulti-infarct dementia three-quarters of patients havefrequent arrhythmias and electrocardiographicchanges of cardiac hypertrophy or coronary arterydisease, whereas in Alzheimer’s disease the ECG islikely to be normal. These findings may, however, beinfluenced by inclusion criteria.Computerised tomographic (CT) scanning is an

essential diagnostic tool in the investigation of

dementia, but cannot be relied upon alone. The

presence of visible infarcts or irregular ventricularoutline will identify the presence of cerebrovasculardisease,20 but the degree of cortical atrophy, size ofcerebral sulci, or presence or absence of ventriculardilatation will not reliably separate vascular and

parenchymal dementia.21-23 Angiography iscontraindicated in hypertensive demented subjects butvascular imaging is sometimes necessary to excludearteritis. The electroencephalographic findings indementia are seldom specific and usually will notdistinguish the cause of illness.The most striking recent observation in Alzheimer’s

disease and related senile dementia has been the

deficiency of neurotransmitters in the brain and

cerebrospinal fluid (CSF) with a loss of cholinergicneurons,24-26 but these findings do not aid clinicaldiagnosis in individual subjects and the concentrationsof dopamine, noradrenaline, and serotonin metabolitesin the CSF will not distinguish the cause of illness.There is great overlap between the various groups ofdementia although concentrations of homovanillic acid

19. Harrison MJG, Thomas DJ, du Boulay GH, Marshall J. Multi-infarct dementia. JNeurol Sci 1979; 40: 97-103

20. Roberts MA, McGeorge AP, Caird FI. Electroencephalography and computerizedtomography in vascular and non-vascular dementia in old age. J Neurol NeurosurgPsychiatry 1978, 41: 903-06.

21. Radue EW, du Boulay GH, Harrison MJG, Thomas DJ Comparison of angiographicand CT findings between patients with multi-infarct dementia and those withdementia due to primary neuronal degeneration Neuroradiology 1978, 16: 113-15.

22 Loeb C. Clinical diagnosis of multi-infarct dementia. In. Amaducci L, Davidson AN,Atuono D, eds. Aging of the brain and dementia. New York Raven, 1980: 251.

23. Somenen M, Puranen M, Riekkinen PJ. Computed tomography findings in seniledementia and normal aging J Neurol Neurosurg Psychiatry 1982, 45: 50-54.

24. Davis P, Maloney AJS Selective loss of central cholinergic neurons in Alzheimer’sdisease Lancet 1976, ii 1403.

25. Gottfries CG, Gottfries I, Roos BE The investigation of homovanillic acid in thehuman brain and its correlation to senile dementia. Br J Psychiatry 1969, 115:563-74.

26. Gotifries CG, Gottfries I, Roos BE Homovanillic acid and 5-hydroxyindoleacetic acidin the cerebrospinal fluid of patients with senile dementia presenile dementia andParkinson’s disease J Neurochem 1969; 16: 1341-45

1312

and 5-hydroxyindoleacetic acid are possibly low insome patients with Alzheimer’s disease, andmeasurement of somatostatin levels in the CSF mayhelp to distinguish Alzheimer’s disease from multi-infarct dementia, but not from pseudo-dementia.16.2s,26The distinction between multi-infarct dementia and

Alzheimer’s disease remains neuropathological ratherthan based on the course of illness and the clinicalexamination. The cardiac findings and CT scan

appearances are of particular value but there is still nosingle diagnostic method apart from brain biopsy thatwill distinguish for certain between these differentdementias. Even if Alzheimer’s disease is not found,the diagnosis is not necessarily one of multi-infarctdisease. However,we can rid ourselves of the notionthat intellectual decline in age is usually due to

hardening of the arteries. Of old people who are judgedincurably demented, between 10% and 20% probablyhave a treatable or at least a static condition, andinvestigation is well worth while.2’

PLASMA EXCHANGE IN THE GUILLAIN-BARRÉSYNDROME

THE Guillain-Barre syndrome or acute idiopathicinflammatory polyradiculoneuropathy (AIP) has an

incidence of 1 to 1 - 5 cases per 100 000 population per yearand this probably does not vary greatly throughout the world.It is thus not a common disorder, but is nevertheless one ofthe more important causes of peripheral neuropathy, withsubstantial mortality and morbidity. Pathologically there aremultifocal areas of demyelination throughout the peripheralnervous system, especially the spinal roots, related to focalinfiltration with inflammatory cells. The myelin is strippedfrom the axons by macrophages. These histological featuressuggest a cell-mediated process for which there is collateral

immunological evidence.’ On the other hand, there is alsoevidence for the operation of humoral factors,1 including thefinding that serum from patients with AIP producesdemyelination if added to tissue cultures or if inoculatedintraneurally in animals. It was therefore natural to explorethe use of treatment by plasma exchange in AIP.

4

The first report of its use was that of Brettle and others2 in1978 in a single case in which improvement was judged tohave been related to the exchange. Other reports ofuncontrolled studies followed, some but not all describingimprovement. 3-6 Controlled studies were therefore

mandatory to avoid the unsatisfactory state of affairs thatfollowed anecdotal reports of improvement produced bycorticosteroids in AIP and which culminated in a controlled

27 Smith JS, Kiloh LG, Ratnavale GS, Grant DA. The investigation of dementia, theresults in 100 consecutive admissions. Med J Aust 1976; ii. 403-05.

1. Arnason BGW Acute inflammatory demyelinating polyradiculopathy. In: Dyck PJ,Thomas PK, Lambert EH, Bunge R, eds. Peripheral neuropathy, 2nd ed.Philadelphia W. B. Saunders, 1984. 2050-100

2. Brettle RP, Gross M, Legg NJ, Lockwood M, Pallis C Treatment of acute

polyneuropathy by plasma exchange. Lancet 1978; ii: 1100.3 Cook JD, Tindall RAS, Walker J, Khan A, Rosenberg R. Plasma exchange as a

treatment of acute and chronic idiopathic autoimmune polyneuropathy-limitedsuccess. Neurology (Minneap) 1980; 30: 361-62.

4. Mark B, Hurwitz BJ, Olanow CW, Fay JW. Plasmapheresis in idiopathic inflammatorypolyneuropathy. Neurology (Minneap) 1980; 30: 361.

5 Ropper AH, Shahani B, Huggms CE Improvement in 4 patients with acute Guillain-Barre syndrome after plasma exchange. Neurology (Minneap) 1980; 30: 361.

6. Rumpi E, Mayr U, Gersenbrand F, Hacki JM, Rosmanith P, Aichner F. Treatment ofthe Guillain-Barré syndrome by plasma exchange J Neurol 1981; 225: 207-18.

trial in which no benefit was detected. 7

The first controlled trial of plasma exchange in AIP was theUK multicentre study8 in which no benefit was found. Yet, inthis trial, several patients were entered who were not in theearlier advancing stage of the disease. In the uncontrolledseries reported by Gross and others,9 a beneficial effect wasobserved only in patients who were still deteriorating. On p1296 of this issue, the results of a controlled Swedish trial arerecorded. The trial was restricted to patients with severeweakness; any who had started to improve were excluded.The study was not blind since sham exchange was notconsidered justifiable. A significant benefit was detected forthe rate and degree of recovery and for the working capacityafter one month. The results of a large American multicentretrial, now complete and shortly to be reported, are eagerlyawaited.

Experimental allergic neuritis can be induced in animals bythe inoculation of heterologous peripheral nerve antigenswith immunological adjuvants. Its clinical and pathologicalfeatures closely resemble those of AIP in man. The

immunological mechanisms are likewise uncertain but againthere is evidence both for a cell-mediated immune reactionand for the operation of humoral factors. Plasma exchangehas been shown to be of benefit in uncontrolled 10 andcontrolled" studies. The nature of the material removed byplasma exchange that results in improvement both in

experimental allergic neuritis and in AIP is still obscure. It isnot necessarily immunoglobulin, for not only are

complement, fibrinogen, and acute-phase proteins removed,but so also are lymphokines and other secretory factors, thedepletion of which might alter the immune response.There is thus mounting evidence that plasma exchange

confers at least some benefit in AIP. What now needs to bedefined is its precise role in management and here the resultsof the large American multicentre trial are likely to be

important. Plasma exchange, in competent hands, is

generally free from major hazard. It is costly, but so is timespent in hospital by patients with AIP. As discussed by theSwedish workers, it would be valuable to be able to predict inadvance those cases that are likely to respond. Probably onlyseverely affected patients will merit plasma exchange-andonly those who are still in the acute progressive phase of thedisease who have not reached a plateau or started to recover. Ifwe could identify the nature of the offending substances thatare removed, this would be of considerable assistance andhere the animal model could provide leads. In addition, cost-benefit equations, not merely in terms of medical risk but alsoin relation to financial demands, are a firm part of

contemporary medicine.There are other syndromes that have affinities to AIP. The

Miller-Fisher syndrome, which consists of acute ophthalmo-plegia, limb ataxia, and tendon areflexia, has been reported tobe benefited by plasma exchange. 12 Other cases exist withclinical and pathological similarities to AIP but with a

chronic relapsing or chronic progressive course. It is now

7. Hughes RAC, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial of

prednisolone in acute polyneuropathy. Lancet 1978; ii: 750-538 Greenwood RJ, Newsom-Davis J, Hughes RAC, et al. Controlled trial of plasma

exchange in acute inflammatory polyradiculopathy. Lancet 1984; ii: 877-799 Gross MLP, Legg NJ, Lockwood MC, Pallis C. The treatment of inflammatory

polyneuropathy by plasma exchange J Neurol Neurosurg Psychiatry 1982, 45:675-79

10. Anthony J, Pollard JD, McLeod JG. Effects of plasmapheresis on the course ofexperimental allergic neuritis in rabbits J Neurol Neurosurg Psychiatry 1981; 44:1124-28.

11 Gross MLP, Craggs RI, King RHM, Thomas PK. The treatment of experimentalallergic neuritis by plasma exchange. J Neurol Sci 1983; 61: 149-60

12 Littlewood R, Bajada S. Successful plasmapheresis in the Miller-Fisher syndrome. BrMed J 1981; i: 778