therelation of syphilis tomental disorder and ...neurosyphilis, apositive reaction of thebloodserum...

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THE RELATION OF SYPHILIS TO MENTALDISORDER AND THE TREATMENT OFG.P.I. BY MALARIA*

By W. D. NICOL, M.B., M.R.C.P.

WHEN the Wassermann reaction was first employedas a routine investigation in mental hospitals, it wasthought that syphilis was intimately related with themental symptoms of the psychotic. As far as thedisease of syphilis itself is concerned, obsessions and fixedideas may occur in the primary stage or produce a condi-tion of syphilophobia; many of these cases, thoughhaving exposed themselves to the risk of infection areactually uninfected and healthy. I have seen three suchcases certified and sent to mental hospitals; they allimproved and were finally discharged, but in two cases,the phobia reappeared with increasing anxiety andcuriously enough both committed suicide by drowning.In the secondary stage of syphilis toxic infection some-times produces a state of mental confusion, with deliriumand hallucinations. Lastly, in the tertiary stage mentalsynmptoms may occur concurrently with cerebral syphilisand indeed give rise to much difficulty in differentiatingthis condition from a very much more definite psychosisand one which is responsible for large numbers of mentalhospital admissions, viz., general paralysis of the insaneor dementia paralytica.

In mental hospital practice apart from general paralysis,syphilitic psychoses are practically non-existent and itcannot be stressed too often that in many cases of mentaldisorder, which do not present neurological signs ofneurosyphilis, a positive reaction of the blood serum (andin a few cases even of the cerebrospinal fluid) is onlyevidence of old syphilis, in no way to be regarded as anatiological factor. Many relatives have been led tobelieve, quite erroneously, that anti-syphilitic treatment

. * Delivered before the M.S.S.V.D. at the Annual General Meeting, July I5th,1933.

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will bring about a recovery, whereas the syphilitic infec-tion has either preceded the onset of mental disease orhas been contracted subsequent to the development of apsychosis. Syphilis in some cases may be regarded as acontributory cause, but excluding the cerebral syphiliticwith mental symptoms and the general paralytic theredoes not appear to be any direct relation between syphilisand insanity.

It is interesting to record that the incidence of syphilisamongst the insane is on the decrease. In I930 *Poynder reported the results of Wassermann tests in 946male admissions to Long Grove Mental Hospital duringa period of five years from June, I924. All tests in theL.C.C. mental hospitals are carried out at the CentralPathological Laboratory and the Long Grove results areof interest, as they are comparable with earlier seriesinvestigated at Cane Hill, by Wootton in I9I3, byMcCowan in I92I, and at Hanwell by Lilly and Hopkins,I923-25.

Wassermann Reactions

Examined. + Wassermann. G.P.I. Non-Paralytics.

Cane Hill . . 284 89 or 3I 66 or 23 23 or I2-5Wootton, I9I3. per cent. per cent. per cent.

Cane Hill . . I50 44 or 29-3 32 or 2I I2 or I0McCowan, I92I. per cent. per cent. per cent.

Hanwell . . 4I2 105 or25 5 50 or I2'I 55 or I5Lilly and Hopkins, per cent. per cent. per cent.

I923-25.Long Grove . . 946 I25 or I3-2 87 or 9 38 or 4-4Poynder, I924-29. males. per cent. per cent. per cent.

In the accompanying table are set out the figuresillustrating the evidence of past syphilis among newadmissions, and these again are subdivided into generalparalytics and non-paralytics. It can be seen that theincidence of syphilis has gradually decreased, being ashigh as 3I per cent. in I9I3 and reaching the compara-tively low figure of I3 per cent. in I924-29. It is notwise, however, to draw any conclusions regarding therelative percentages of general paralytics, the yearspreceding malaria therapy show little variation, but thelow figures for recent years do not necessarily mean that

* Poynder, Journal of Mental Science, LXXVI., p. 107, I930.220

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RELATION OF SYPHILIS TO MENTAL DISORDE R

G.P.I. is a less common disease, because since the adventof malaria therapy, cases of G.P.I. have been concen-trated at two or three mental hospitals in the L.C.C.service, where treatment is conducted. The greaterincidence of non-paralytics at Hanwell may be explainedby the theory put forward by Mott, that syphilis is moreprevalent in the West End of London, from whichdistrict the majority of Hanwell patients are drawn.Yet with an indication of a decrease in the number of

syphilitics amongst admissions for the insane, one mightexpect that the incidence of G.P.I. should be down also.Through the courtesy of the Board of Control I have hadaccess to figures giving the total number of generalparalytic admissions to mental hospitals in England andWales between the years I907-3I. While stressing thefact that my views in no way represent those of the Boardof Control, very great caution should be exercised beforedefinitely concluding that G.P.I. is on the decrease. Withfemale admissions (first attack) the ratio of generalparalytics to total admissions remains fairly constant.Though the total number of male G.P.I.s has graduallybecome smaller during the last ten years, it is impossibleto draw any definite conclusions without being able toeliminate other factors. For instance, it has become thefashion in recent years to treat many cases in generalhospitals instead of certifying them and sending them tomental hospitals.

Before the days of malaria therapy the early diagnosisof general paralysis was of little import ; sooner or later adoubtful case would become established by its clinicalcourse and sooner or later, despite any effort at treatmentby anti-syphilitic measures the case would die; in fact,with few exceptions cases died within one to three yearsfrom onset of symptoms. In males the end might comewith startling rapidity, a fatal issue supervening within afew months. Now that we have at our disposal a meansof treating what hitherto was regarded as a fatal diseaseit is all important that G.P.I. should be diagnosed andconfirmed as early as possible. The confirmation of adiagnosis demands a positive reaction of the cerebro-spinal fluid, yet here a word of warning is necessary,every case with a positive C.S.F. and superadded mentalsymptoms must not be labelled as a case of G.P.I. Lastyear when reviewing the results of malaria therapy in

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women over a period of seven years, it was found that36 cases could not be included in the total, as they werenot suffering from general paralysis, yet they presentedpositive sera and C.S.F. The syphilitic infection, exceptin the cases of meningovascular syphilis must be regardedas latent and not related to the psychosis. Six weretabetics with psychoses (3 delusional insanity, 2 melan-cholia, and i schizophrenia) ; amongst the others wereold cases of epilepsy, manic depressives, confusional typesof insanity, alcoholics, schizophrenics, a case of seniledementia, a Huntingdon's chorea, five showed varyingdegrees of dementia with gross brain lesions and sevenfrom the history and neurological signs were cerebralsyphilitics. With the exception of the cases of cerebralsyphilis, gross brain lesion and the tabetics, these casesdid not present any signs suggestive of neurosyphilis.

Psychoses somewhat resembling general paralysis arenot uncommon in association with cerebral syphilis; thedifferentiation of this condition from the more serious oneof general paralysis is often difficult. The symptomsof the cerebral syphilitic yield rapidly to energetic anti-specific treatment and indeed to malaria therapy itself,whereas the disease of general paralysis is progressivein character and uninfluenced by antispecific remedies.An important point in differentiation of these conditionsis the length of duration of symptoms. The onset ofG.P.I. is insidious, that of cerebral syphilis rapid. AsColonel Harrison says: " The patient glides into generalparalysis while he jumps into ordinary cerebral syphilis."The length of time (if a reliable history is obtainable) thathas elapsed between the primary attack and onset of latersymptoms is seldom less than six years in G.P.I., whereasin cerebral syphilis it is the reverse.

Reliance should be placed on the physical signs; theyare more definitely localised in cerebral syphilis; ocularparalysis is common. The cerebral syphilitic frequentlygives a definite history of an attack of syphilis; thegeneral paralytic often quite honestly denies ever havinghad an attack, or if he did the attack was very mild.Secondary reactions are the exceptions, not the rule. Inmental hospitals, cases of cerebral syphilis are com-paratively rare, only seven in seven years at Horton.

It might be convenient here to say a few words aboutthe diagnosis of G.P.I. The mental symptoms are so

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RELATION OF SYPHILIS TO MENTAL DISORDER

protean in character, that in the early stages diagnosispresents considerable difficulty. There is an early stagein which the patient is often free from physical signs, butwith the all-important fact of syphilitic changes in theC.S.F. Too often an alteration in character is the firstsymptom with loss of finer habits and without anyobvious sign of insanity. Bunker * analysed 74 early casesand found the following symptoms in order of frequency:emotional irritability, restlessness, abnormal quietness andapathy, loss of weight, forgetfulness, increased tendencyto sleep, defective judgment. All these symptoms arevery vague. Much depends on the individual skill of theclinician. Anyone between the age of thirty to fiftywho has indefinite neurasthenic symptoms should beexamined for G.P.I., also anyone who suddenly developsfits in middle life. The practitioner is too often easilysatisfied with a diagnosis of neurasthenia or epilepsy. Inall these cases a Wassermann of the blood and C.S.F.should be done. It is not uncommon nowadays to comeacross cases with negative sera. The C.S.F. shouldalways be examined in any doubtful case and if the caseis one of general paralysis, the C.S.F. will be positive withan increased amount of globulin, which gives rise to thetypical paretic colloidal gold curve. As the case pro-gresses mental symptoms become more marked and it ispossible to classify cases into different types-thegrandiose exalted form, in which delusions of grandeurand wealth are the prominent features, the maniacalagitated form, in which restlessness and increasedpsychomotor activity predominate, the depressed form,characterised by the presence of delusions of persecution-often of a somatic nature, the affective state being theantithesis of that in the former group, and lastly the simpledementing form, in which general mental reduction ismore obvious. By this time one or more of the physicalsigns may be present Argyll Robertson pupils in somecases, tremors of tongue and lower part of face with aloss of expression, increased tendon reflexes (except inthose cases accompanied by tabes), slurring of speech, anextremely valuable sign of it occurs early in the course ofthe disease, and in those cases not complicated by tabesa shuffling unsteady gait.

Before giving a brief account of the results of malaria* American Journal of Medical Science 1926, p. 386.

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therapy at this hospital, I would point out that they dealwith female general paralytics only. During the lasteighteen months, facilities have been available for thetreatment of male cases, but it would be prematureto include the small number so far treated. Thoughsufficient evidence has not yet been adduced, one hasgained an impression perhaps erroneous-that G.P.I.in the male is a more serious disease, not only does themale case appear more physically ill than the female, buthe does not withstand the course of malaria so well.The results are based on a review of 200 female cases

treated during the previous seven years.* It is not pro-posed to go into too much detail here, nor to burden youwith unnecessary figures, but rather to point out somesalient facts that have emerged from our experience andto say a little about the treatment itself.On analysis of the cases, it was found that the grandiose

maniacal and depressed cases were numerically smallergroups, compared with the total of the simple dementingtype. All cases, with the exception of twenty-four,received malaria alone. The percentage of dischargedcases was about 35 per cent., which compares favourablywith the figures of other workers. The number of thoseremaining in hospital was high (40 per cent.), while thedeaths which occurred during the seven years were low(25 per cent.).There are three important factors which appear to

influence the results: the duration of the disease beforetreatment, the clinical type of G.P.I., and the reaction tobody weight. It was found that the highest percentageof remissions occurs in those cases where the disease istreated in the early stages, three-fifths of good remissionswere confined to cases who received their treatment in thefirst six months. Disappointments occur and it is signifi-cant that while 45 per cent. of the cases of six months'duration recovered, 55 per cent. remained under certificatein hospital. Another feature of interest is the case whoremits, when the disease has been established over twoyears. Treatment, then, should not be despaired ofaltogether. With regard to the clinical types theprognosis appears to be definitely better for the grandiosemanic and depressed cases, 50 per cent. of these show

* A review of seven years' malaria therapy in general paralysis. W. D. NICOL.Journal of Mental Science, LXXVIII., Oct., I932.

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remissions. In the simple dementing cases even in thoseof short duration not more than 25 per cent. recover andthe remission rate rapidly falls with increased durationof disease. Some of the treated cases show rapid increaseof weight and it was found that this abnormal weightincrease was confined to the cases which showed noimprovement. A very useful prognostic factor emergedfrom our results and that was, almost a constant limitcould be assessed with regard to the time of recoveryafter treatment. Nearly all cases, if well enough to bedischarged from certificate and to return to the outsideworld, were able to do so within seven to nine monthsfollowing a course of malaria; in fact, if a case is notmentally well by that time the prognosis should be veryguarded. Only a very few cases received a supple-mentary course of anti-specific treatment or tryparsamide,but even with this small number and from the experienceof other workers, supplementary treatment is indicated,the life of the patient is prolonged and the recovery ratein some series is higher.Of those cases which do not improve sufficiently to

leave hospital, in many the progress of the disease isarrested, while in others there is little change or gradualdeterioration. In quite two-thirds of total numberstreated physical improvement is marked and the patientat least has a happier and cleaner existence than fell tothe lot of the untreated cases of pre-malaria days. Fromthe psychological point of view, it is of interest to see thechanging form of psychosis in some cases-schizoidreactions and an acute hallucinatory psychosis, hithertoforeign to the original progressive deterioration of thedisease. Malaria treatment undoubtedly prolongs lifefor the general paralytic. Out of Io8 cases treated atHorton between I925 and I928, 70 per cent. are still alive.In the Board of Control series investigated by Meagher,of 624 untreated general paralytic admissions in I923,go per cent. were dead by the end of I927.The mortality rate in induced malaria still remains

high, varying from IO to i5 per cent., and if death occurswithin six to eight weeks, following the inoculation,malaria, if not the actual cause, is undoubtedly held to beindirectly responsible.The risk of mortality would be reduced, if cases were

sent for treatment in the very early stages, before the225

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disease has progressed. In our series at Horton themortality rate has become gradually lower; in benigntertian over a period of seven years it was 5 per cent.,in a series of over sixty cases treated by malignanttertian malaria the mortality rate was not more than4 per cent. It should be mentioned that selection wasaimed at with the M.T. cases, in those treated by B.T. noselection was made. Yet risks must be taken in treatinga disease which, if left alone, will surely prove fatal. Itis obviously courting disaster to treat an advanced semi-bedridden case, or a case in which there is some seriousheart lesion (aortitis in G.P.I. however is extremely rare);marked obesity in a patient often causes considerableanxiety during treatment. It is surprising how manycases will pick up with ordinary hospital treatmentafter a few weeks; the mere fact of being kept in bedand given a nourishing diet will restore a case to acondition sufficient to withstand malaria. The mainsecret of success lies in efficient nursing, such as onecan obtain at a centre like this, coupled with expertlaboratory control in examining blood films regularly.This, together with the interruption of fever whennecessary, should prevent impending risks. We havefound one dose of 5 grains of quinine sufficient foraborting an attack, it produces a remission of feverfrom ten to fifteen days, during which time the patientis regaining his strength, it has the advantage that thefever recurs, generally with less severity. What are theindications for temporarily interrupting the fever ? Ifall is not well with a patient, anxiety is generally feltabout the fourth or fifth day-continued hyperpyrexia,a persistent high pulse rate after the temperature hasfallen, faintness or collapse during the paroxysm, per-sistent vomiting, the occurrence of seizures, undue rest-lessness and the earliest signs of jaundice, also a changeof the intermittent character of fever to a remittent type,are regarded as signals that the course should be inter-rupted. Digitalis as a prophylactic against cardiaccomplications and gentian and soda for vomiting areuseful adjuncts, but the practice of giving a small doseof quinine during fever and knowing when to give ithas in my opinion rendered malaria, a safe procedure.At Horton, on account of malaria research conducted

in conjunction with the Ministry of Health, one has had226

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the opportunity of trying different species of malaria-benign tertian, quartan, malignant tertian and P.ovale have all been employed. The therapeutic valueof one particular species does not appear to be superior toanother, but this cannot definitely be concluded until onehas access to a much larger group of cases treatedprimarily by malignant tertian or quartan in order tocompare them with the already big number treated bybenign tertian malaria. Malignant tertian is too severeto use promiscuously; it was given a trial on the hypo-thesis that the fever was more severe and the sporulatingparasite had a predilection for the brain capillaries.Quartan is definitely useful for the case which is immuneto benign tertian; moreover, it can be given to a mucholder and more debilitated type of case with absolutesafety. If the case runs true quartan, the length of timerequired for a course of treatment may be a drawback,on account of expense involved and time lost, which tothe private case or the general hospital patient may be all-important. Benign tertian malaria, with the doubletertian fever, which occurs in most primary cases of B.T.malaria, is much quicker, the whole course for an uncom-plicated case being over in ten to fourteen days.The employment of different species of malaria ren-

dered it possible to give those cases of general paralysiswhose mental condition did not respond to the firsttreatment a second course of fever. As one species ofmalaria does not confer immunity against anotherspecies, it was thus possible to give patients a secondcourse of treatment, which was as severe as the firstcourse. A patient who had B.T. could have M.T.,quartan or ovale and so one could ring the changes andgive a second or even a third treatment. Unless itimproves their physical condition, the results are franklydisappointing, and I have failed to record any mentalimprovement except in those cases where the secondcourse was applied in the first six months following thefirst. It seems almost certain that if a patient does notrespond to the first treatment by malaria, he will notrespond at all.Now how does malaria act ? In our present state of

knowledge this question appears unanswered and we mustfall back on the idea that the treatment is mainly empiri-cal. Yet we have been able to discover two important

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facts-the alteration in the serology of the treated patientand the appearance of the brain. Last year thirty-twofluids of unimproved cases were examined at the CentralLaboratory at the Maudsley. Two years at least hadelapsed since the primary attack of malaria. All caseshad strongly positive findings before treatment; I7returned a negative Wassermann and in io it wasmarkedly reduced. These results are of interest, as themalaria alone must be responsible for this. None ofthese cases had any supplementary antispecific treatment,but there does not appear to be any correlation betweenthe serological reactions and the clinical result. I havealso had the opportunity of inducing malaria in two orthree cases (not general paralytics) with an obstinatelypositive blood serum (in spite of ordinary antispecificmeans), and in each case the serum after a course ofmalaria has become negative.

Histologists are in agreement that the treated paralyticbrain presents an altered picture. Geary,* who for manyyears has examined brains at the Maudsley and Clayburylaboratories, writes that before the days of malariatherapy Mott found spirochaetes in the brain in 66 per cent.of general paralytics. Forty-two brains of generalparalytics treated at Horton have been examined andthe results are tabulated in the accompanying table.

Forty-two General Paralytic BrainsHistological Examinations.

Total. Spiro- Total.chaetes + +. Perivascular SlightChanges. Changes. No Change.

Treated 31 2 I8 7 2 9(i Cong. (2 Cong.)

Untreated. II 3 Io 6 3(2 Cong.)

The absence of the characteristic perivascular changesin most of the treated cases is marked. In this seriesare included four congenital cases and it is noteworthythat treatment in these cases produced no pathologicalimprovement. Spiroch.etes were present in only one

* Geary, " Histopathology of General Paralysis," Mott Memorial Volume,I929.

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acquired case which had received treatment. The casewas treated in I925 and had a good remission, lastingfour years; on her readmission she showed markedmental deterioration and her physical condition was toopoor to withstand further treatment.

In view of the serological and histological findings onemust admit that malaria has done more to produce thesechanges than any other mode of therapy.

In spite of education of the public to the dangersincurred in contracting venereal disease and the estab.lishment of V.D. clinics, and in spite of energetic anti.specific treatment in the primary stages, there is noguarantee against the subsequent development of nervousand mental symptoms which necessitate certification,Ordinary antispecific measures are not prophylacticagainst the onset of G.P.I. In the application of malariato medicine, have we got a prophylactic against syphilisof the nervous system ? Surely the latent case withpersistently positive changes in the cerebrospinal fluid isa potential G.P.I., and in these, as in other cases withobstinately positive sera, is not a course of malariaindicated ? Malaria has been adopted by some workersas a therapeutic agent for primary syphilis in additionto routine arsenic treatment, and time alone can tellwhether these cases will be protected from developimga disease, which even now, is responsible for manyincurable insane.

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