TRYPARSAMIDE IN THE TREATMENT OF SYPHILIS OF THE …Inthepresent series there werefive patients...

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TRYPARSAMIDE IN THE TREATMENT OFSYPHILIS OF THE NERVOUS SYSTEM*

By FRANK E. CORMIA, M.D., Instructor of Dermatology andSyphilology, School of Medicine, University of Pennsylvania,

Philadelphia.

TRYPARSAMIDESINCE tryparsamide was synthesised by Jacobs and

Heidelberger eighteen years ago there has evolved aslowly changing conception of its modus operandi. Theearly experimental studies by Brown and Pearce, in whichthey predicted the principal actions of tryparsamide inhuman infections, were followed by the basic clinicalinvestigation, by Lorenz and his co-workers, of the valueof tryparsamide in the treatment of syphilis of the centralnervous system. One significant fact immediately becameapparent, namely, that late central nervous systemsyphilis, which had previously resisted long sieges ofstandard treatment for syphilis with arsphenamine,neoarsphenamine, the various intraspinal techniques,and mercury and the iodides, was now responding to thisnew form of treatment.

MECHANISM OF ACTION OF TRYPARSAMIDEThe exact mechanism of the action of tryparsamide is

unknown. It stimulates natural resistance and has awell-recognised tonic effect. It has, as Moore has shown,no spirochaeticidal action in man; and he found itabsolutely valueless in primary, secondary and tertiarysyphilis of the skin, and in osseous or visceral syphilis.The effectiveness of tryparsamide depends, I believe,

upon its superior penetrative power for the tissues of thecentral nervous system. Voegtlin arrived at this con-clusion indirectly, deducing it chiefly from the fact thattryparsamide was therapeutically effective with rabbitswhose brains were infected with trypanosomiasis.

* From the Department of Dermatology and Syphilology, School of Medicine,'University of Pennsylvania, Philadelphia, Pa., John H. Stokes, M.D., Director.

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BRITISH JOURNAL OF VENEREAL DISEASES.

Mehrtens, and later Cornwall, Bunker and Myers, esti-mated the amount of tryparsamide penetrating thecerebro-spinal fluid. Mehrtens reported large amounts,while Cornwall et al. found only relatively small amounts.Fordyce et al., working with rats, tried to determine theamount of arsenic in dried brain substance. Theyconcluded that tryparsamide had no penetrative powerfor the nervous tissue. Osborne, however, has made avery pertinent criticism, and believes that " one cannottell how much arsenic is present in the blood of an organafter death, how much blood is in the organ, and howmuch arsenic has penetrated the cellular tissue of theorgan." Working with a micro-chemical method ofestimation of the number of crystals of arsenic trioxideseen in a given section of prepared tissue, he apparentlydemonstrated that, following the administration oftryparsamide, appreciable amounts of arsenic werepresent in the parenchyma of the brain and spinal cord.It would seem then, as Solomon has stated, that tryparsa-mide has a local effect, working within local areas of thenervous system, but just what that effect is we do notknow.

MATERIAL AND METHODS OF THE PRESENT STUDYThis series is composed of 75 cases of neurosyphilis.

Of these 75 cases, 44 form the basis of this study, andhave each received more than twenty injections oftryparsamide. The total number has been used onlyin estimating the percentage of ocular damage. Of the44 cases completely studied, 33 were males and ii werefemales. The average duration of the disease when thepatient was first seen was:

(a) 9.7 months in six patients with early neurosyphilisand

(b) Sixteen years in 38 cases of late neurosyphilis.The average duration of treatment with tryparsamidewas two years, the average number of injections oftryparsamide was fifty-eight. Injections were given,with but few exceptions, continuously, and at weeklyintervals. From one to five courses of an insolublebismuth preparation, each course consisting of approxi-mately twenty injections, were given concomitantly inmost of the cases. All of the cases had previously received

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TRYPARSAMIDE IN TREATMENT OF SYPHILIS

varying amounts of standard treatment for syphilis,seven had received typhoid vaccine (with very littlebenefit), three had received malaria, and three othershad been treated by the Swift-Ellis method.

RESULTS OF PRESENT STUDY, IN COMPARISON WITHTHOSE OF PREVIOUS INVESTIGATORS

(i) Early Neurosyphilis.Tryparsamide therapy has been only partially effective

and reliable in early neurosyphilis. Moore and his co-workers have cited several muco-cutaneous and neuro-relapses from their early material. Moore, Stokes,O'Leary and Solomon routinely give prolonged standardtreatment with arsphenamine and bismuth. However,Solomon states that " If cases with early nervous systeminvolvement, with a paretic type of serology, do notrespond to standard therapy, they should be placed atonce on tryparsamide or malaria, if definite late neuro-syphilis is to be avoided."

Hopkins, in a recent analysis of the Johns Hopkinsmaterial, found an 85 per cent. clinical and a 64 per cent.serologic cure. But these percentages apply to treatmentwith standard, followed by tryparsamide, therapy.

In the present series there were five patients with earlyneuro-syphilis, in each of whom a paretic type of spinalfluid had been obtained. The average number of tryparsa-mide injections was sixty-six. Each patient had pre-viously been treated with considerable amounts ofarsphenamine and heavy metal. In three patients thespinal fluid ultimately became negative, in one it wasreduced and in one it was unchanged. One patientwho had previously received sixty-one injections ofbismarsen, four of old arsphenamine and forty of bismuthdeveloped a left facial paralysis and a paretic type ofserologic relapse after forty-nine injections of tryparsa-mide. The paralysis soon cleared, and the spinal fluidbecame negative after fifty-five more injections oftryparsamide. Another patient who had previouslyreceived thirty-four injections of arsphenamine (6o6),twenty-three injections of bismuth and seventy-sixmercury rubs had a paretic type of serologic relapse afterI04 injections of tryparsamide.

(2) Meningo-vascular Syphilis.IOI



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Results obtained by previous Investigators

Clincallimprved Serologic cure orClinicallyimprrved, marked improve-orarrested. ment.Per cent. Per cent.

Moore . . 90 I00Lorenz . . . I00 9oCady . . . 98 6 +Solomon . 90 go +Schwab . . . 8o

90 85

There was only one patient with meningo-vascularsyphilis in the present series. Previous therapy consistedof six injections of neoarsphenamine and thirteen ofbismuth. Seventy-five injections of tryparsamide weregiven, and the patient when last seen had been clinicallyimproved, but only the cells in the spinal fluid had beenreduced to normal. The protein, Wassermann andcolloidal mastic were unchanged.

(3) Tabes dorsalis.Results obtained .by various Investigators

Clinical cure or Serologic cure orNumber of cases. niarked improve- marked improve-

ment. ment.

Per cent. Per cent.Schwab . . . 20 56 70Lorenz . . . . I4 54 65O'Leary. . . 25 22 40Moore . . 24 50 85Cady . . . 74 45 50Hopkins . . . 20 29Present series . . . 6 50 83

Average . . 42 58

Tryparsamide is less effective in Tabes dorsalis thanin other froms of neurosyphilis. There is a considerablediscrepancy, as the above table indicates, between theclinical and the serologic results. Tabes dorsalis is a latedegenerative process with permanent nerve damage.The tryparsamide arrests the active syphilitic process,as is shown by the higher percentage of serologic reversals,

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but the impairment of function is caused by previousnerve damage, and clinical progression is the rule. Solo-mon states that ".Cases with marked degeneration do notrespond well. A completely negative spinal fluid, indi-cating a burnt-out process, as is present in some of thelate clinically active cases, makes the prognosis even lesssatisfactory. Yet tryparsamide is of definite value, andshould be given a thorough trial in selected cases, asclinical improvement sometimes occurs after manymonths of therapy."

(4) General Paresis.Results obtained by various Investigators

Number of cases. Clinical improve- Serologic improve-ment. ment.

Per cent. Per cent.Schwab and Cady . . 63 74 68Moore . . . . 57 77 83Holmes . . . . 64 go 50O'Leary. . . . 65 6o 53Hinsie and Blalock . . 6o 4I.7Hopkins . . . 20 40Ebaugh and Dickson . 52 29Stokes and Wilhelm . II4 57 8oLorenz . . . II7 54 40Present series . . . 37 63 75

57 59

In paresis tryparsamide again seems to arrest, in a largeproportion of cases, the active syphilitic process in theparenchymatous tissue. In general it may be statedthat the percentage of clinical and serologic arrest variesinversely with the age of the patient, the duration of theparenchymatous involvement and the degree of pre-existing damage. Stokes, in a previous report, predictedthe relatively poor results that were to be obtained inpatients with the late deteriorated types of generalparalysis. Hinsie and Blalock, working with institu-tionalised paretics, found a considerable discrepancybetween the clinical and serologic improvements, thepercentage of serologic improvement being much higher.Solomon and Lorenz obtained serologic reversals in alarge percentage of institutionalised paretics, but founda very low percentage of clinical improvement. The

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active process had been checked, but the past damagewas irreparable. On the other hand, Stokes and Solomonhave observed that juvenile paresis, a fairly late andextensive type of involvement, responds well clinicallyto tryparsamide, although the spinal fluid often cannotbe reversed to negative.

Comparison of Clinical ImprovementLate Paresis

in Early and in

Early. [ Late.

Per cent. Per cent.Stokes o.9 25Lorenz . . 84 25Present series . 66 40

Women, as Hinsie and Blalock have noted, respondmore favourably than do men. In the present series62 per cent. of the eleven women underwent a completeserologic and clinical cure, while in only 46 per cent. ofthe men was complete serologic and clinical cure obtained.

Serologic Results in Spinal Fluid in General Paresis inPresent Series

Compl. Reduction.

Type. No. reversal Unchanged.cases. toColnegative. Protein. Cells. Wass. mastic.Per cent. Per cent. Per cent. Per cent. Per cent. Per cent.

Asymptomatic . 8 66 17 17 I7 I7 17Early or moderately ad-

vanced . . . i8 56 i8 29 15Tabo-paresis . . 6 50 33 33 i6 i6 17Late paresis . . 4 None 50 50 25 _ 50Juvenile paresis . . I None - 100

37 50

As the above table indicates, the more advanced andthe more extensive the process, the lower is the percentageof serologic improvement. The clinical response injuvenile paresis was excellent, there being a markedweight gain, feeling of well being, and increase in mentalacuity. But there was no improvement in the spinalfluid after I29 injections of tryparsamide.

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PROLONGED TREATMENT WITH TRYPARSAMIDEAs is well known, clinical improvement occurs early

during the course of treatment with tryparsamide;improvement of the spinal fluid takes place much moreslowly. The initial changes are reductions in the numberof cells and in the amount of protein; reduction of thecolloidal reaction and of the Wassermann test takes placemore slowly.

Effect of Varying Amounts of Tryparsamide upon theSpinal Fluid in General Paralysis

Per cent. rendered niegative.No. No.

cases, inijections. GouCells. Globu- Wass. Colloidal test.

Stokes and WVilhelm:Early paresis . 21 20 71 20 10 48Late paresis 23 20 100 30 13 39

Tennent* . I1I 50-100 40 40 20 40Bunker 7 75-II5 - 100 0 0

Solomon and Viets t 5 75-125 8o 20 80 20 (Red. in 8o)t 5 125-I8o 8o 6o 6o 6o( ,, ,, 40)

Moore, Stokes, O'Leary and Solomon especially haveinsisted that treatment with tryparsamide must beprolonged. Solomon has cited instances in which serologicreversal to negative has taken place only after the two-hundredth injection of tryparsamide. He has given morethan 300 injections, over a period of more than eightyears, in resistant cases, and considers that completereversal of the spinal fluid to negative is the only reliablesign of cure.

Accordingly, an effort was made in the present studyto determine the effect of prolonged treatment withtryparsamide. The spinal fluid findings were plotted,first against the number of injections given to the wholegroup, and second against the number of injections givenin the different clinical types of general paresis. Inneither instance was there any definite correlation be-

* Seven of these eleven cases failed to improve with tryparsamide and weretreated with malaria. Of these seven, the spinal fluid became negative in onlythree.

t Of this group-the spinal fluid became negative in only three cases, althoughthe clinical results were very good. The spinal fluids ol the other seven caseswere all improved, but in two instances I48 and I83 injections of tryparsamidefailed to reverse the spinal fluiid Wassermann reaction to negative.

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tween the serologic response and the number of injectionsgiven. There seems to be some unknown factor in manycases of general paralysis which determines the type ofresponse to tryparsamide therapy. Occasionally trypar-samide will produce neither clinical nor serologic improve-ment in cases in which it would seem to be the idealmethod to use. In this series were three patients, onewith early clinical paresis and two with asymptomaticparesis, who simply would not respond to ioo injectionsof tryparsamide.

THE QUESTION OF SEROLOGIC AND CLINICAL RELAPSEIn this series are five cases of relapse. Two were those

of early neuro-syphilis, already discussed; the third case,one of early paresis, after having received forty injectionsof tryparsamide, was placed on a rest interim of sixmonths. A spinal fluid examination after the rest revealeda paretic type of serologic relapse. After thirty moreinjections of tryparsamide the spinal fluid findings wereunchanged. After her ninety-fourth injection she becamevery excitable and mentally confused, but then lapsedfrom view, preventing further observation. The fourthcase was one of early paresis, who had been dischargedas well (clinically and serologically) after seventy-oneinjections. He returned three years later complainingof speech difficulties, nervousness and poor memory.A spinal fluid examination revealed a paretic type ofserology-Wassermann 4444, globulin four plus, cellssix and colloidal mastic 55543IIOOO. He subsequentlylapsed from view. The last case was one of moderatelyadvanced paresis. He received seventy-nine injectionsof tryparsamide, following which his spinal fluid hadbecome negative and his clinical status had improvedmarkedly. Ten months later a routine blood Wassermanntest was returned strongly positive. As it had beennegative for the previous year another spinal fluidexamination was made, with the following result: Wasser-mann 4444, cells i6, globulin four plus, colloidal mastic555542iooo. His clinical status at the time was good,and after preparatory treatment with mercury and iodideshe was given eight injections of tryparsamide. He thenlapsed from view. Two months later he was admittedto the mental division of the hospital with marked mental

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deterioration and confusion. He was subsequently givenmalarial therapy, with some clinical but no serologicimprovement.

In the three cases just cited there was no intercurrentinfection, either general or focal. There was no instanceof severe nervous strain. And so here again, and for noapparent reason, the response to prolonged treatmentwith tryparsamide could not be predicted by a carefulselection of patients in whom this method of therapywould seem to be ideal.Many. investigators (Jahnel, Grimaldi, Sioli, Hall,

Belezky and Grant) have stated that there is a definitecorrelation between the clinical course of general paralysisand the spirochaetes in the brain cortex. These spiro-chaetal showers, or crises, are most frequently observedin the acute fulminating and in the juvenile types ofparesis. Hauptman, however, has observed that inpatients dying with acute seizures spirochaetes are aptto be few in number, or may be actually absent. Hebelieves that the seizure- is an anaphylactic one and isevidence of true allergic sensitivity. On the other hand,some of the cases of intense spirochetosis such as Dieterlehas described seem to be entirely accidental autopsyfindings.

Grant and Aberol found very few spiroch?etes in thebrains of cases treated with tryparsamide or malaria anddying from other causes. In the acute fulminating forms,when such therapy was ineffectual, many spirocheteswere found. It may be, then, that the presence of largenumbers of spirochetes in the brain increases the re-sistance of the disease process to tryparsamide therapy,but before this can be definitely accepted, the conceptionsof individual immunity and susceptibility, of bacterialallergy, and of the neurotropic strains of the spirochaete,must first be clarified.

TRYPARSAMIDE THERAPY AND THE BLOOD WASSERMANNREACTION

There is one other unexplained phenomenon whichoften occurs during the course of tryparsamide therapy.This is the frequently observed reversal to negative ofthe blood Wassermann reaction. It sometimes occursearly, sometimes after two or more years of treatment.

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Moore states that " tryparsamide has little or no effect onthe blood Wassermann reaction." Although I have noway of proving the converse, I believe that the spiro-chawtes in the brain may be partially if -not entirelyresponsible for the positive blood Wassermann.; In themore fulminating type of case the spirochaetes aregreatly increased in number, the reaction to them ismore intense and the blood Wassermann reaction isusually strongly positive. On the other hand, whentryparsamide has actually effected the disappearance ofthe spiroch?etes from the cortical tissue the blood Wasser-mann 'usually becomes negative. In this connection itmay be noted that improvement in the blood Wassermannreaction roughly parallels that in the spinal fluid, and aserologic relapse in the spinal fluid is usually, although notalways, accompanied by a corresponding one in the blood.

It is interesting to note that in cases of paresis resistantto tryparsamide not only. does the spinal fluid Wasser-mann reaction remain strongly positive, but the proteinand the cells of the spinal fluid are rather constantlyincreased.

Most of the cases in the present series also receivedbismuth therapy. This may have had some effect on theblood Wassermann reaction, especially if there wereactive antibody-forming centres outside of and irrespec-tive of the central nervous system. Lastly, one must notforget the spontaneous tendency of the blood Wassermannreaction to become negative. While this factor can, Ibelieve, be minimised in cases in which the involvementis primarily of the central nervous system, it must bekept in mind as a possible factor in such instances.

Percentage Reversal of Blood Wassermann ReactionPer cent.

Moore . . . . . 28Stokes and Wilhelm . . . 39O'Leary . . . . . IOTennent . . . . 36Williford . . . . * 7ILorenz . . . . . 99Hinsie and Blalock . . . 44Present series . . . . 47

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ACTION OF TRYPARSAMIDE UPON THE OPTIC MECHANISMTryparsamide has, as is well known, a definite toxic

action on the optic nerve mechanism, producing in a smallproportion of cases a toxic amblyopia. Mild degrees ofdamage are accompanied only by subjective symptoms,the most common of which are failing, dim or dazzlingvision and flashes of light, clouds or flickering before theeyes. The more severe degrees of damage are accompaniedby objective signs, viz. : (i) diminution of visual acuity;(2) constriction of the visual fields and, less important,(3) beginning pallor of the nerve head.

Percentage of Eye Damage by Tryparsamide *

Percent. of Subjective Objective PermanentNo. cases, ions. symptoms. findings. eye injury.

Previous authors . 986 8-o, 6-i 4i5I6

Present series . 75 8. 6-6 45 I3-3 4,5 I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-3

The possibility of optic injury can be reduced to aminimum by a careful ophthalmologic control for the firstten weeks of therapy. This consists of a careful perimetricexamination of the visual fields, the taking of visualacuity and an examination of the nerve head. Opticinjury is rarely produced by tryparsamide after the tenthinjection. The subjective symptoms are importantwarning signs and call for a repeated and careful searchfor signs of objective damage, and discontinuance of thedrug for thirty days. When only slight signs of objectivedamage have appeared and further use of the drug seemsurgently to be indicated, tryparsamide is only temporarilywithheld (permanently, however, if damage is severe) andsodium thiosulphate is given intravenously. For markedfield constriction, Casten has recommended forced spinaldrainage as described by Kubie. This consists of two tofour lumbar punctures performed at intervals of two tofour days. At each puncture IOO to 200 C.C. of spinalfluid is removed, while the patient simultaneously

* Compilation of estimations by Woods and Moore, Lillie, O'Leary, WVile,Lorenz, Stokes and Wilhelm, Schwab and Cady, Ebaugh and Dickson, Solomon,Holmes and Tennent.

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receives a hypotonic solution intravenously. We havehad no experience of this form of treatment.The exact cause of the eye damage is unknown. Many

authors (Stokes, Moore, O'Leary) feel that the toxicaction of tryparsamide is increased when the optic nerveis devitalised by pre-existing damage. Lillie, on the otherhand, has stated that tryparsamide is no more injuriousto the optic nerve than is arsphenamine (606). Young,Pearce and Loevenhart suggested that a too rapid resolu-tion of the granulomatous tissue of neuro-syphilis mayelaborate toxins which may produce or aggravate a pre-existing optic lesion.

Sattler, Birch-Hirschfeld and Igersheimer have shownthat eye damage by the pentavalent type of arsenicalremedies (atoxyl) is done principally to the third neurone ofthe optic nerve. Sattler stated that the poison had its firstpoint of attack on the third neurone, i.e., in the portionfrom the ganglion cell layer of the retina to the externalgeniculate body. Schwalbe believed that tryparsamidewas concentrated in the spinal fluid, then reached theoptic nerve vid the subvaginal space, which communicateswith the subarachnoid space. The spinal fluid surroundsthe optic nerve from the lamina cribrosa to the opticforamen, the point of reflection of the brain membranesover the optic nerve. As the point of contact with thespinal fluid corresponds to that portion of the nervewhich is most affected, it is conceivable that the damageis done in this manner. If the optic nerve has beenpreviously damaged, it may be that a Herxheimer reac-tion in these involved areas may be responsible for theconsequent symptoms which we term toxic amblyopia.This belief has crystallised into a gradual therapeuticapproach with mercury, iodide and bismuth, followedby an initial I-gm. dose of tryparsamide. This gradualapproach, however, has not always been successful, aswill be shown in the following statement on optic atrophy.Lazar has recently suggested that the toxicity of tryparsa-mide may be an allergic type of reaction, depending on aspecific anaphylactic reaction to the tryparsamide itself.

In the present series, subjective symptoms wereobserved in nine patients. In seven instances there wereno accompanying objective signs, and tryparsamidetherapy was resumed after a two-week interval. In twoinstances subjective symptoms were warning signals of

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beginning objective damage.. The first patient complainedof blurring and fine flashes in front of the eyes. Thevisual fields were moderately constricted, and tryparsa-mide was withheld for two weeks. The symptoms andfield constriction had by then disappeared, and tryparsa-mide therapy was resumed without further trouble. Thesecond patient was a rapidly advancing case of paresisassociated with gastric crises. Her spinal fluid had becomedefinitely worse on bismarsen, she had become intolerantto old arsphenamine (606) and she was placed on try-parsamide. The vision began to fail in the left eye afterthe ninth injection of tryparsamide. The ophthalmologicexamination was negative, and it was felt that she shouldreceive the benefit of tryparsamide if she could tolerateit. She persistently complained (for eight weeks) ofgradually failing vision, but only after the seventeenthinjection was definite field constriction and diminutionof visual acuity observed. Tryparsamide therapy wasthen discontinued permanently. Subsequent examina-tions by the ophthalmologists revealed that the atrophywas of the primary type. It gradually progressed inspite of intraspinal therapy, and at the time of writingthe patient is receiving as a last resort fever therapy.Just what, if any, was the r6le of the tryparsamide inhastening this most disconcerting progression is difficultto determine.

Objective signs of damage were present in four instancesin 75 cases. In one patient this was observed after thesecond injection of tryparsamide, and in the second afterthe fourth injection. Tryparsamide was withheld fortwo weeks, by which time the signs of injury had dis-appeared, and therapy was gradually resumed withoutfurther trouble. The third patient developed contractedfields after the tenth injection of tryparsamide, and thefields subsequently improved, but did not become normalagain (although vision was unaffected), and so therapywith tryparsamide was not resumed. The last patientwas one with previous primary optic atrophy due tosyphilis, and will be reported fully in the followingparagraph. One other patient deserves recording; hepresented moderately constricted fields at the onset oftreatment; vision was excellent, and the visual fieldshad become normal after the tenth injection of tryparsa-mide.

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Tryparsamide Therapy in Optic Atrophy

Cady, in I930, recorded the effect of tryparsamide inpatients with pre-existing eye involvement and made thesurprising observation that in i6 cases of primary -opticatrophy due to syphilis I2 per cent. were definitelyimproved and 50 per cent. were arrested by tryparsamidetherapy. In ten patients with cohtracted fields 66 percent. were either arrested or improved. Lees, followingthe suggestion of Cady, has used tryparsamide in 'thetreatment of'2Icases of syphilitic optic atrophy. 'In' over50 per cent. of the cases he secured a complete arrest, andthe patient was able to resume his occupation.' Therewas no effect in 3 cases, and in 6 cases the tryparsamidewas discontinued b'ecause of developing signs 'of furtherdamage.We have treated only 2 cases of optic atrophy with

tryparsamide. One patient, who was almost completelyblind when'first seen, was unaffected by either twentySwift-Ellis treatments or by fifty injections' of tryparsa-mide. The other, who had a moderately 'advancedatrophy, suffered a marked field constriction after receiv-ing 0o5 gi. tryparsamide, although he had previouslyreceived mon'ths of preparatory treatment with bismuth.Tryparsamide was permanently withhel'd, and the' fieldssubsequently recovered to the degree obtaining whenfirst observed.

Tryparsamide therapy of optic atrophy is still in theexperimental stage, and should be- carried out cautiously,if at all, and then only at the hands of those to whom anadequate ophthalmologic control is available.

COMPLICATIONS OTHER THAN OCULARThe literature records few complications, probably in

part from incomplete' reporting. There has been oneinstance of exfoliative dermatitis, five of jaundice, one ofhemoisrhagic disease ;due to bone marrow change, twonitritoid' reactions, and one' Jarisch-Herxheimer reaction(acute irritability and mania). Recently Robinsonreported a case of fixed tryparsamide eruption, the onlyone in the literature.

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after tryparsamide injection, but, in neither instance wasdiscontinuance of the drug necessary.

There was one case of jaundice associated with an en-larged liver. Tryparsamide therapy was subsequentlyresumed without further trouble.

There was one instance of the so-called Herxheimereffect, the patient becoming more irritable and nervouswith successive injections. This effect disappeared afterthe tenth injection.

In the present series only one severe early reaction wasobserved. The patient, one with early asymptomaticparesis, began to have headaches after his injection oftryparsamide. This was first noted after the sixthinjection and gradually became more severe. Immediatelyafter the twenty-sixth injection, in spite of the use of the"Bezredka " technic and the preliminary injection ofy- grain of. atropine sulphate, he developed. a severetypical nitritoid attack. Tryparsamide therapy wasresumed after a five months' interval, but after thefourth injection he developed a second nitritoid attack,this one much more severe than the first and requiringthe use of adrenalin. The patient refused further tryparsa-mide therapy.

There were two cases of early cardiovascular involve-ment, signs of which developed while the active processin the brain was slowly responding to treatment. Ineach case standard therapy for syphilis had previouslybeen given, but in insufficient amounts. One case didnot receive bismuth during the tryparsamide therapy,while the other patient received only twenty-six injectionsof a bismuth preparation. The lesion in each instancewas an early aortitis. This well emphasises the impor-tance of giving concomitant courses of an intramuscularbismuth preparation, especially in those patients whohave not previously received an adequate amount ofstandard treatment for syphilis.

CONCLUSIONS(i) Tryparsamide is an excellent drug in the treatment

of late syphilis of the central nervous system.(2) Clinical improvement occurs early, and the clinical

outcome in cases of early paresis is roughly paralleledby the serologic outcome in the spinal fluid.

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(3) This series confirms the well-known belief that theclinical outcome is in inverse ratio to the duration of thedisease and to the amount of pre-existing damage.

(4) The response of the spinal fluid was in this seriesonly very roughly in direct proportion to the amount byweight of tryparsamide given. It seemed to dependmore on the duration of and the amount of previousdamage done by the disease. Complete return of theabnormal cerebro-spinal fluid to normal was obtained in66 per cent. of the cases of asymptomatic paresis, in56 per cent. of those patients with moderately advancedparesis, in 50 per cent. of the cases of tabo-paresis andin none of the cases of late paresis. The spinal fluidfindings remained strongly positive in one case of juvenileparesis.

(5) The spinal fluid was reversed to negative in approxi-mately 50 per cent. of the present series, most of whichwere cases of asymptomatic or early paresis. Solomonfound that the spinal fluid was returned to normal in35 per cent. of a cross section of all types of paresis. Thisdifference in percentage illustrates the advantage ofinstituting treatment in the asymptomatic stage of generalparesis.

(6) Complete clinical arrest and return to normal ofthe spinal fluid occurred in 62 per cent. of the women,as compared with 46 per cent. of the men.

(7) The action of tryparsamide could not always beabsolutely predicted, even in those instances in which itwould seem to be the ideal type of therapy. In three suchinstances there was no improvement with tryparsamide.

(8) Rarely, as Ravaut has observed, ultimate reversalof the spinal fluid to normal occurs. One patient whosespinal fluid was strongly positive at the end of fiftyinjections of tryparsamide was again examined after alapse of three years; the spinal fluid had become com-pletely normal without further treatment.

(g) In one instance serologic relapse (of spinal fluid) wasthe forerunner of clinical relapse.

(io) Permanent eye injury occurred in this series inI-3 per cent. of cases. No complete amblyopia occurred.

(ii) There were two instances of early aortitis develop-ing during tryparsamide therapy.

(i2) One severe nitritoid reaction was observed. Thisis the second reported case in the literature.

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