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

1313

clear that plasma exchange improves some cases of chronicrelapsing inflammatory polyneuropathy.3,13-15 The improve-ment is temporary but may persist for some weeks and suchcases can be managed by repeated exchanges. Benefit in casesof chronic progressive inflammatory polyneuropathy is lessconspicuous. ]5,]6 Plasma exchange is also of little assistancein those cases of chronic relapsing inflammatorypolyneuropathy where there is extensive axonal destructionand denervation rather than predominant demyelination. 17

ERGOT FOR DEMENTIA?

CO-DERGOCRINE mesylate, better known by its proprietaryname of’Hydergine’, is a mixture of the mesylates of the ergotalkaloids dihydroergocriptine, dihydroergocornine, and

dihydroergocristine. In clinical use for over thirty years, ithas been the subject of many dozens of clinical trials; yet itstherapeutic activity remains controversial. The most

important claim is for its efficacy in the treatment of dementiain the elderly.Like other ergot alkaloids, hydergine has complex

pharmacological actions. In thecentral nervous system, it isa mixed dopaminergic agonist and antagonist, and is an

antagonist at a-adrenergic receptors. It may also be both anagonist and an antagonist at serotonin receptors. Some ofthese properties, together with the interaction of the drugwith peripheral receptors, contribute to the vasodilatoreffect. Indeed, the drug is widely used as a hypotensive. Inaddition, Loew2 has suggested that hydergine influencesneuronal and glial intermediate metabolism and oxygenconsumption. The vasodilator effect is no longer consideredto be of primary therapeutic importance in this context. Themechanism of any beneficial effect of hydergine is

controversial, as are many other aspects of this drug. Clearly,most of these mechanisms would be very difficult to

demonstrate in human beings.Whatever the relevant mode of action might be, there has

been a widespread belief that hydergine may arrest, or evenpartly reverse, the progress of dementia in elderly patients.Macdonald3 has summarised 38 double-blind trials of

hydergine, in which it was mostly compared with placebo butalso with drugs such as papaverine and multivitamin

preparations. The great majority of the patients were inhospitals or old people’s homes and the mean age was about76 years. Very severely affected patients were generallyexcluded, as were those with post-traumatic or post-infectivebrain damage or intracranial neoplasms. In almost all cases,clinical rating scales were used-notably, the Sandoz ClinicalAssessment Geriatric Scale. In about two-thirds of the studies

psychometric testing was done as well; and, in a very few,electroencephalograms (EEGs) and cerebral blood flow

13. Levy RI, Newkirk R, Ochoa J. Treatment of chronic relapsing Guillain-Barré

syndrome by plasma exchange. Lancet 1979; ii: 741.14. Server AC, Lefkowith J, Braine H, McKhann EM. Treatment of chronic relapsing

inflammatory polyneuropathy by plasma exchange Ann Neurol 1979; 6: 258-61.15 Gross MLP, Thomas PK. The treatment of chronic relapsing and chronic progressive

idiopathic inflammatory polyneuropathy by plasma exchange. J Neurol Sci 1981,52: 69-78.

16. Toyka KVR, Augspach R, Paulus W, Grabensee B, Hem D. Plasma exchange mpolyneuropathy Ann Neurol 1980; 8: 205-06

17. Pollard JD, McLeod JG, Gatenby P, Kronenberg H. Prediction of response to plasmaexchange in chronic relapsing polyneuropathy. A clinicopathological correlation. JNeurol Sci 1983; 58: 269-87.

1 Berde B, Sturmel E. Introduction to the pharmacology of ergot alkaloids and relatedcompounds as a basis for their therapeutic applications. In: Berde B, Schild HO, eds.Ergot alkaloids and related compounds. Berlin: Springer, 1978: 1-28.

2. Loew DM. Pharmacological approaches to the treatment of senile dementia. InAmaducci L, Davison AN, Antuono P, eds. Ageing of the brain and dementiaAgeing, vol 13. New York: Raven Press, 1980: 287-94.

3. Macdonald RT. Drug treatment of senile dementia In. Wheatley D, ed

Psychopharmacology of old age. Oxford: Oxford University Press, 1982: chap 9.

measurements are reported. In all these studies hydergineimproved the rating scales for depression, anxiety, andemotional lability. There was also some effect on confusion,short-term memory, and alertness. Most of the papers reporta statistically significant global improvement in clinical state,as assessed subjectively by the investigators; but on

psychometric testing the benefits of treatment are much lessclearcut. Hollister and Yesavage’ have drawn attention to theconsiderable differences in results reported by differentinvestigators. Rehamm5 suggests that hydergine has no effectat all on psychological status.5 Gaitz et al6 describe definiteimprovement in cognitive and intellectual function.6 AndYesavage and co-workers 7 believe that apparentimprovements in such functions are secondary to

improvement in mood, alertness, and motivation.It is not surprising that evaluation of this drug and similar

agents has proved difficult. Most investigators now believethat trials of hydergine and similar agents are likely to be mostvaluable in patients with dementia of the Alzheimer type orwith multi-infarct dementia, and that these two groupsshould be carefully distinguished when the results are

analysed. Hollister4 suggests that only patients with earlydementia-in other words, those who are not in an institution-are likely to benefit from any type of pharmacologicalintervention, and this may well be a realistic view. However,early dementia is very easy to miss. A widespread use of ratingscales is understandable, but can be misleading. Increasingly,functional disability scales, such as those used in theassessment of Parkinson’s disease, are being used in theevaluation of hydergine and similar drugs.8 The clinicalimport of changes in psychometric tests or in the EEG is alsounclear. There are other difficulties in assessing the results sofar obtained. In virtually all the papers cited by Macdonaldthe hydergine doses were 4 - 5 mg daily or less, although up to8 mg daily was given in one. Such doses may well be too low,9particularly since the bioavailability of the drug is variableand low, averaging about 10%.*° The amount reaching thebrain is likely to be very small after oral dosage, even if iteffectively penetrates the blood-brain barrier (which we donot know).Most clinical trials of hydergine have been brief. Of those

listed by Macdonald, the great majority lasted 12 weeks,while some were even shorter; only four lasted longer than 6months. Studies of such short duration may be inadequate inassessing efficacy in a chronic and usually slowly progressivecondition such as senile dementia. One important aspect ofthe drug should be emphasised at this stage-its good safetyprofile. Hydergine has little emetic activity in man, and,unlike some other ergots, does not cause peripheralvasoconstriction. Orthostatic hypotension is rarely severe ordose-limiting.

4. Hollister LE, Yesavage J Ergoloid mesylates for senile dementias unanswered

questions. Ann Intern Med 1984; 100: 894-98.5. Rehamm SA. Two trials comparing "Hydergine" with placebo in the treatment of

patients suffering from cerebrovascular insufficiency. CurrMed Res Opin 1973, 1:456-61

6. Gaitz CM, Varner RV, Overall JE Organic brain syndrome in late life. Arch GenPsychiatry 1977, 34: 839-47

7 Yesavage JA, Westphal J, Rush L Senile dementia: combined pharmacological andpsychologic treatment. J Am Geriatr Soc 1981, 29: 164-71

8. Lazzari R, Franzese A, Chienchetti SM, Vibelli C, Rudelli G, Passeri M, Lulinotta D.Multicenter double-blind placebo-controlled long-term clinical trial of Hyderginein chronic senile cerebral insufficiency: an interim report. In Agnoli A, et al, eds.Ageing, vol 23: ageing brain and ergot alkaloids. New York Raven Press, 1983:347-71.

9 Yoshikawa M, Hirai S, Aizawa T. A dose-response study with dihydroergotoxinemesylate in cerebrovascular disturbances. J Am Geriatr Soc 1983, 31: 1-7.

10. Woodcock BG, Loh W, Habedank WD, Tietbrock N. Dihydroergotoxine kinetics inhealthy man after intravenous and oral administration. Clin Pharmacol Ther 1982;32: 622-27.