I DEVELOPMENTS IN THE TREATMENT OF SYPHILIS WITH ... · of clear-cut progressive paralysis, butis onewithalatent positive spinal fluid, requiring prophylactic treatment. Alsothosesickpeoplewhocanstill

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DEVELOPMENTS IN THE TREATMENT OFSYPHILIS WITH ARTIFICIAL FEVERTHERAPY COMBINED WITH CHEMO-THERAPY DURING THE PAST

DECADE"Fever is a mighty engine which Nature brings

into the world for the conquest of her enemies,"-SYDENHAM (I 624-I689).

By WALTER M. SIMPSON, M.D., F.A.C.P.,* H. WORLEYKENDELL, M.D, and DONALD ROSE, M.D.

Director, Associate Director and Research Associate, Respectively, ofthe Kettering Institute for Medical Research, Miami Valley Hospital,

Dayton, Ohio, U.S.A.

INTRODUCTIONON May 22, I936, it was the privilege of one of us

(Simpson) to deliver an address before the MedicalSociety for the Study of Venereal Diseases on " ArtificialFever Therapy of Syphilis and Gonococcic Infections."The published address appeared in The British Journal ofVenereal Diseases for July, I936. The report was basedupon observations made during a five-year study of theapplication of artificial fever therapy to various diseaseprocesses. At the conclusion of the lecture an invitationwas extended to members of the Society to visit theKettering Institute for Medical Research for the purposeof observing the work at first hand. The invitation wasaccepted by Mr. Ambrose J. King, F.R.C.S., a Vice-President of the Medical Society for the Study of VenerealDiseases, after conferences with Colonel L. W. Harrison.Colonel E. T. Burke, Dr. Arthur H. Harkness and othercolleagues. Mr. King came to Dayton for a period ofseveral weeks of observation and instruction during thespring of 1937. A report of Mr. King's experiences,entitled " Fever Therapy at Dayton, Ohio," appeared in

* Honorary Member of the Medical Society for the Study of Venereal Diseases;Special Consultant, Division of Venereal Diseases, U.S. Public Health Service;Commander, Melical Corps, U.S. Naval Reserve.

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BRITISH JOURNAL OF VENEREAL DISEASES

the British Journal of Venereal Diseases for October, I937.Mr. King also observed the work in artificial fever therapyat the University of Rochester, at the University ofPennsylvania and at several clinics in New York City.He also attended the International Conference on FeverTherapy in New York City in March, I937. Shortlythereafter, work in this field was launched at the LondonHospital (Whitechapel Clinic), utilising the Ketteringhypertherm, under the directorship of Mr. King. Thework was progressing with eminently satisfactory resultswhen it was interrupted abruptly by the exigencies ofwar.The present report has been prepared in response to a

request received from Colonel Harrison for a criticalreview of developments in the use of artificial fevertherapy in the management of syphilis, including a furtherreport of our work in this field during the past ten years.

I. NEUROSYPHILISFortified by the experiences of a decade it can now be

stated that artificial fever therapy * of neurosyphilis isat least as effective as malaria therapy. The past fiveyears have witnessed a notable decline in the hyper-enthusiastic and sometimes extravagant claims made bycertain advocates of one or the other method. Out ofthe controversy has emerged a more rational clarificationof the relative merits of the two procedures. Severalrecent authoritative communications have contributedto this wholesome situation.

APPRAISAL OF MALARIA THERAPY AND ARTIFICIAL FEVERTHERAPY BY WAGNER-JAUREGG

The brilliant analysis of " The Present Management ofProgressive Paralysis," by Julius Wagner-Jauregg, pub-lished in I939 (i), a short time before his death, is amasterpiece of unprejudiced objectivity. After examin-ing critically the results attained with malaria therapy andwith artificial fever therapy, Wagner-Jauregg, the fatherof malaria therapy, made these significant statements:"The method of treatment by elevation of body tem-

* The term " artificial fever therapy" denotes the production of fever byphysical means.

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perature to the height of fever by physical means has beenused in a large number of diseases and has been shown tobe very valuable. In so far as used in progressiveparalysis the methods concur with malaria therapy .Results show that after treatment of progressive paralysis(with physically induced fever) there were remissionssimilar to those which occur in patients treated withmalaria. Also many have found that treatment ofparalytics with physically induced fever gave a numberof full remissions as great or greater than with malaria.The number of improvements was equally good.

" Furthermore, it is a well-known advatntage of artificialfever that one can regulate the height of the temperaturereached, the length of the fever period and the lengthof fever-free rest periods according to the condition of thepatient. Moreover, during the course of treatmentcontinuous hospitalization is not necessary. The lastspecial consideration occurs when a case that is not oneof clear-cut progressive paralysis, but is one with a latentpositive spinal fluid, requiring prophylactic treatment.Also those sick people who can still continue their orderedbusiness life require several weeks of interference withtheir work if malarial treatment is used. Finally, iffollowing artificial fever and chemotherapy, the goal oftreatment is not reached, namely, the production ofnegative spinal fluid, then one still has time to utilizemalarial treatments . .

" A few weeks after the ending of the fever treatmentit is the rule that one can determine if a full remission isto be expected and those having an unfavourableprognosis can be called back. It is fortunate that thepossibility exists to change the type of fever treatment;accordingly, a malarial treatment may be substituted forartificial fever or vice versa.

" Too little use is made of divided malarial treatments.In this type, after three or at the most four attacks offever the malaria is controlled by quinine. Then afteran interval during which specific treatment is carried out,a new malarial inoculation is made. The patient in themeantime has recovered and can better tolerate longertreatments than during the first half of the course. Suchdivided methods can be carried out more easily withartificial fever."Admitting that experience has determined from a

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great amount of material that malaria and artificial fevercombined with intensive treatment with pentavalentarsenicals gives on the average the same number, degreeand length of remissions there must also be non-medicalconsiderations in the choice of the method. One mustobserve the question from an economic standpoint. Sofar as the fever-producing agents are concerned themalarial treatment has an unquestioned advantage. Thelittle cubic centimeter of blood which is necessary for thetreatment of paralytics costs nothing, and even supposingthat the material for injection comes from another placethere is no important cost. Furthermore, sick personscan be treated together in a room under supervision of atrained nurse or orderly. The artificial fever apparatusis costly. During the course of a treatment the uninter-rupted presence of a person trained in the complextechnic of the apparatus is necessary. Also only as manycases may be treated simultaneously as there is availableequipment."Truly one advantage of the artificial fever treatment

must be brought forward, namely, that it is innocuouscompared to the danger of malarial treatment (as regardsfatalities)."

REPORT OF COMMITTEE ON NON-SPECIFIC THERAPY OFSYPHILIS, U.S. PUBLIC HEALTH SERVICE

In August, I936, about three years before Wagner-Jauregg's classic report appeared, Dr. Thomas Parran,Surgeon-General of the U.S. Public Health Service,appointed a sub-committee of the Co-operative ClinicalGroup to study and to evaluate the various forms of non-specific therapy used in the treatment of neurosyphilis.This committee was composed of Dr. Paul A. O'Leary(Chairman), Mayo Clinic, Rochester, Minnesota; Dr.Walter L. Bruetsch, Central State Hospital, Indianapolis,Indiana; Dr. Franklin G. Ebaugh, University of ColoradoPsychopathic Hospital, Denver, Colorado; Dr. HarryC. Solomon, Boston Psychopathic Hospital, Boston,Massachusetts; Dr. Stafford L. Warren, University ofRochester, Rochester, New York; and one of us(Simpson). All had had extensive experience with eithermalaria therapy or with artificial fever therapy or withboth. Dr. R. A. Vonderlehr, Assistant Surgeon General,

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Division of Venereal Diseases, U.S. Public Health Service,was also a member of the committee and was assisted byMiss Lida J. Usilton, I. V. Sollins, A. P. Iskrant andother members of the Statistical Division of *the U.S.Public Health Service.

In addition to submitting to the U.S. Public HealthService for statistical analysis clinical records from allof the institutions represented by the members of thecommittee, the following clinic directors offered foranalysis the records from their institutions: Dr. A. E.Bennett, University of Nebraska, Omaha; Dr. HaroldN. Cole; Western Reserve University, Cleveland; Dr.J. R. Blalock and Dr. Leland E. Hinsie, New York StatePsychiatric Institute, New York City; Dr. Frank R.Menagh, Henry Ford Hospital, Detroit; and CaptainErnest H. Parsons, M.C., U.S. Army, Fitzsimons GeneralHospital, Denver.

It required nearly four years to collect the data and tosubject it to rigid analysis by disinterested professionalstatisticians. The report of the Committee, on " Malariaand Artificial Fever in the Treatment of Paresis,"appeared in Augiist, I940 (2). The study was designedto compare the therapeutic results obtained by the useof artificial fever produced by physical methods withthose obtained by the use of inoculated malaria in thetreatment of paresis (dementia paralytica). The resultswere evaluated in terms of both clinical and serologicresponses observed after the independent use of eithermethod of fever therapy, with or without the associatedemployment of chemotherapy.Only unequivocally paretic patients who had been

observed for more than two years following the com-mencement of fever therapy were considered. Therecords of I,420 such patients were pooled for statisticalstudy. Of these, i,Ioo patients were treated with malariaand 32o with artificial fever.

All were classified by the degree of syphilitic meningo-encephalitic involvement when fever therapy was begun.Patients with " mild paresis " were relatively free fromsigns of deterioration and their mental symptoms wereusually transitory. Those classified as having " inter-mediate paresis" exhibited symptoms of manic excite-ment, depression or other psychiatric syndromes, inaddition to evidence of moderate deterioration. The

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third classification, that of " severe paresis," includedthose who gave evidence of advanced deterioration.The clinical results of therapy were defined as:

(a) 'remission," in which there was sufficient clinicalrecovery to permit the patient to return to his formersocio-economic status; (b) "improved," which denotedcomplete or partial disappearance of clinical manifesta-tions without corresponding improvement in the capacityto return to the former socio-economic status;(c) " unimproved," in which there was no detectableclinical evidence of change in the course of the disease;(d) " progressed," which indicated that the clinicalstatus was less satisfactory after treatment than before;and (e) " death," which included deaths during therapy,or deaths regardless of cause occurring within threemonths subsequent to therapy.

CHART X

CNe@VHCr"APVrTRYPARSAMIDE AtIDMEAVY METALS.

1926-1931

4ALA41A FOLLOWEDSY CHEMOT P._P C

1931-1936 4XPERcEArRES15 1 0

ARTIFICIAL FLVIRCOMAINED WIJW AND ASESFOLLOWED by CNEMO- fPERgv_Sr HUE APY .

1934,-1939

The 70 cascs inctude 30 from fhc University ofcebraska Fever Therapy Research Department havin9 Sb percent romissions, and 40 commi/ted paretics at W4astingsStat llospial , includinq 12 chronic malarial failures,with 47.5 per cent remIssions.

The yearly clinical remission rates per IOO patientstreated were cumulated by the method of therapy andby the degree of paretic involvement when fever therapy

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a PER cEtyr REM15510tiSI

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was begun. Thus, the total successful results of therapywere determined at the conclusion of any given yearwithin the entire period of treatment and post-therapyobservation. The increase in the percentage of successfuloutcomes of therapy within a given year could thus beobtained by subtraction (Table I.).

TABLE I.-AVERAGE YEARLY CLINICAL REMISSION RATES(CUMULATED)

(Committee on Non-Specific Therapy of Syphilis, U.S.Public Health Service)

THREE-YEAR TREATMENT-OBSERVATION

Rate of Remission per Ioo Paretics under Treatment-Observation.

Endof each Year Mild.. Intermediate. Severe. Total.Observation.

Malaria. Artificial Malaria. Artificial Malaria. Artificial Malaria. ArtificialFever. Fever. Fever. Fever.

I 36-4 37 7 I3-7 I6-2 0°0 3.9 I3-8 i8-o2 45.I 48&4 202 2PO 0.5 9-o I8-9 24-73 51P7 502 24-2 23-6 0 9 II-3 22-4 27-2

FOUR-YEAR TREATMENT-OBSERVATION

I 36-4 35-2 I3.3 i6*8 0.0 2*9 I3-4 I6-92 44 7 45.9 i9@6 I9-2 0.5 8-6 I8.4 22-63 5I.9 47.3 23 5 22O0 I°II0 3 2I-9 25-I4 52 3 52-8 25.I 309 IP0 II.3 22-8 30 3

As regards the patients with mild or intermediateparesis there were no statistically significant differencesbetween the rates of remission obtained with malariatherapy and those obtained with artificial fever therapy.In other words, equally good clinical results were obtainedfollowing either method of fever therapy in patients withmild or intermediate paresis. Sharp and statisticallyreliable differences were noted, however, between theresults of the two methods of therapy among patientssuffering from severe paresis at the beginning of fevertherapy; here there was distinct superiority of remissionrates following artificial fever therapy, as noted in Table I.The clinical responses were best when fever therapy

was instituted early in the course of the disease. Thus,7



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at the end of three or four years of treatment-observation,more than one-half of the patients with mild paresistreated with either method of therapy had clinicalremissions. Similarly, with either method of fevertherapy, the rates for clinical recovery were reduced toapproximately one in four patients with intermediateparesis. While the proportion of remissions was dis-tinctly less in patients with severe paresis, ii per cent. ofpatients with severe paresis obtained clinical remissionafter artificial therapy, while only i per cent. had clinicalremission following malaria therapy.

For purposes of this study, treatment deaths weredefined as deaths occurring not only during the course offever therapy but also included all who died regardlessof cause -during the succeeding three months. Utilizingsuch criteria, the total crude death rate was higher withmalaria (I3 per cent.) than with artificial fever (8 percent.). The frequency of death was greatest among thepatients with severe paresis (25.8 per cent. of malaria-treated cases and I7-9 per cent. of those treated withartificial fever). By contrast, among patients with mildparesis there were no deaths during the course of artificialfever therapy and four deaths during malaria therapy;2-3 per cent. of the patients with mild paresis treated byeither method died within three months. Among thosewith intermediate paresis, 9.4 per cent. of the malaria-treated patients and 6-5 per cent. of those treated withartificial fever died during treatment or within threemonths following treatment. Thus, while these indi-vidual differences are not statistically significant, theyall point in the same direction in indicating that thepercentage of deaths under malaria therapy was higherthan with artificial fever therapy within each degree ofparetic involvement.An analysis of the relative speed with which remissions

were attained revealed that approximately go per cent.of the successful results occurred by the end of the thirdyear by either method. In mild paresis remissions wereobtained from one to two years earlier than in inter-mediate or severe paresis.

If clinical improvement was delayed beyond the secondyear following fever therapy by either method remissiondid not occur. Thus, the more prompt the clinicalresponse, the better was the prospect for eventual

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remission. Once clinical remission was obtained, thechances of its being maintained were 95 out of 100.There was no statistically valid difference in the relapserates following either method of fever therapy.

In determining the relation of clinical to serologicresults, it was found that clinical success was not accom-panied by complete serologic reversal (of blood and ofspinal fluid), in more than one-half of the cases. Thus,emphasis is again given to the fact that successful clinicaloutcome is not necessarily dependent upon serologicresponse.

Regardless of the method of therapy, the percentagesof serologic reversal rates -of both blood and spinal fluidincreased as the duration of the treatment-observationperiod grew longer, Positive blood reactions reversed morerapidly though not in greater proportion than positivespinal fluid reactions. The percentage of blood reversalswas greater in the malaria-treated group, but reversaloccurred more rapidly in those treated with artificial fever.The necessity for employing auxiliary chemotherapy

with either method of fever therapy was indicated by boththe significantly higher proportion of spinal fluid reversalsand by the maintenance of such reversals in patientsreceiving concomitant or subsequent chemotherapy orboth. In patients treated with fever plus chemotherapythe annual rates of reversal of spinal fluid reactions frompositive to negative as well as the rates of blood reversalwere higher with malaria than with artificial fever, butthis difference was assumed to be due to the greateramount of chemotherapy (I7 per cent. more) administeredto the malaria-treated patients. Without the use ofauxiliary chemotherapy there were no differences betweenthe spinal fluid and blood' reversal rates of patientstreated with malaria and those treated with artificialfever. The reversal rates of blood and spinal fluid wereapproximately twice .as great with as without the use ofauxiliary chemotherapy. Among patients not receivingauxiliary chemotherapy 42 per cent. of all spinal fluidreversals subsequently relapsed, as contrasted with24 per cent. spinal fluid relapses among patients treatedwith auxiliary chemotherapy.

In three-fourths of the cases in which both clinical andserologic recovery were reported, clinical remission eitherpreceded serologic reversal or occurred during the same

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year. When clinical remission preceded serologicreversal, the average difference in time was between twoand three years.A correlation of the clinical outcome with the duration

and the intensity of fever, measured by rectal temperaturelevels, left no doubt that there was a definite correlationbetween the height and duration of fever and the clinicalresults. The highest percentage of clinical remissionswas obtained in the two groups of patients who experi-enced either an average of 69 hours of fever above IOI F.(38.3 C.),* of which 70 per cent. was at a level aboveI05 F. (40.6 C.) with a maximum temperature .of io6-9 F.(416 C.) ; or in those who received an average of 44 hoursof fever above ioi F. (38.3 C.) of which total time 57 percent. were above io6 F. (4I-I C.) with amaximum tempera-ture of I07 F. (4I17 C.). On the other hand, the clinicalresults were distinctly inferior, to the point of beingpractically nil, in those patients who received an averagetotal of 30 hours above IOI F. (38.3 C.), with an averageof I2z8 sessions of 2 hours comprising the total course,with a maximum temperature of I04-9 F. (40.5 C.), andwith an average of 26 per cent. of the total fever time ata level between I04 and I04-9 F. (40 to 40 5 C.). Acareful analysis of the data revealed that no clinicaladvantages were gained by submitting patients to rectaltemperatures above io6-5 F. (414 C.). The Committeewas unanimous in its belief that temperatures betweenio6-5 and Io6-7 F. (414 and 415 C.) are apparently thehighest rectal temperature levels which can be usedwith safety in clinical practice, and then only whensurrounded by adequate safeguards. Experience hastaught that the administration of fever therapy at levelsabove Io6-7 F. (415 C.) introduces unnecessary hazards.

REPORT BY EWALT AND EBAUGH, UNIVERSITY OFCOLORADO, DENVER, OF TREATMENT OF ALTERNATEPATIENTS WITH ARTIFICIAL FEVER OR MALARIA

In his classic appraisal of the relative advantages ofartificial fever and malaria therapy, Professor Wagner-Jauregg (i) directed particular attention to a preliminaryreport (3) published by Barnacle, Ebaugh and Ewalt of the

* Throughout this report all statements regarding body temperature refer torectal temperature levels, usually obtained by constantly indicating or recordingelectrical thermometers.

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University of Colorado Psychopathic Hospital in I936,of a comparative study of artificial fever therapy combinedwith and followed by tryparsamide, and of malariatherapy followed by tryparsamide. Wagner-Jaureggreferred to the procedure adopted by Barnacle, Ebaughand Ewalt as " an excellent plan " for " an equalizedinvestigation of fever therapy by the Kettering hyper-therm and by inoculation with malaria."The Denver investigators, who had had long experience

with malaria therapy, decided to employ the " alternatecase " method of determining the comparative usefulnessof artificial fever therapy and of malaria therapy. Strictalternation was practised in assigning successive patientsto one or the other therapeutic program. The samecriteria as those adopted by the Committee on Non-Specific Therapy of the U.S. Public Health Service (ofwhich Professor Ebaugh was a member) were used inclassifying paretic patients as " mild," " intermediate "or " severe." Thus, the advantages were had of unity ofmaterial, time, place and observers.

In the preliminary report (I936) of the therapeuticresults accruing from this controlled study of 6o patientsduring a one year period, it was stated that in theartificial fever-chemotherapy group (30 patients) therewas remission in I2 (40 per cent.), as compared withremission in 7 (23.3 per cent.) of the 30 malaria-chemo-therapy patients. Nine (30 per cent.) of the patientstreated with artificial fever-chemotherapy were improved,while I2 (40 per cent.) of the malaria-chemotherapypatients responded likewise. Thus, of those treatedwith artificial fever, 2I (70 per cent.) were benefited, ascompared with a similarly favourable outcome in I9(63.3 per cent.) of the malaria-treated patients. Nopatients died during the course of artificial fever, butone patient died of cerebral hoemorrhage two weeks -afterthe apparently successful conclusion of the course offever treatments. One patient died during malariatherapy and 3 malaria-treated patients died during theyear following treatment.Here again it was found that the highest proportion of

remissions occurred among patients with " mild " paresis.Improvement in spinal fluid serology was comparable inboth groups and there was no parallelism between clinicaland serologic improvement.

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In a current report (4), Ewalt and Ebaugh provide addi-tional information regarding the progress of the originalgroups of patients and submit data on a five-year com-parative study of artificial fever therapy and malariatherapy, bases upon the assignment of 232 patients withdementia paralytica either to artificial fever therapy orto therapeutic malaria. The authors were encouragedto continue the comparative study of alternate pareticpatients because of the favourable results obtained withartificial fever therapy ii the original series, and todetermine if possible why " for reasons not entirely clearto the authors, certain clinics treating neurosyphilis havebeen skeptical of the therapeutic value of artificial feverin this neuropsychiatric disorder."As the work at the Colorado Psychopathic Hospital

progressed it became apparent that certain pareticpatients who were not considered to be candidates formalaria therapy because of such concomitant disordersas cerebral arteriosclerosis, chronic nephritis or diabetes,could tolerate artificial fever therapy if due caution wasexercised. Hence, the only deviation from the " alternatepatient" plan in the more recent study was to include37 such patients in the group treated with artificial feverand auxiliary chemotherapy. Thus, the totals arebrought to I34 patients treated with artificial fevertherapy and to 98 patients treated with malaria.The comparable character of the two groups as regards

the type of fever therapy administered to patients in thedifferent clinical categories is shown by the fact that 44(or 32 per cent.) of the patients treated with artificialfever and 3I (or 3I per cent.) of the malaria-treatedpatients were classed as " severe," while 70 (or 52 percent.) of those treated with artificial fever and 55 (or55 per cent.) of those treated with malaria were classifiedclinically as "intermediate." The average age ofpatients treated with artificial fever was 40 years and theaverage age of those treated with malaria was 42-6 years.The duration of symptoms prior to the institution offever therapy was 22-8 months in the artificial fevertherapy group and I7-2 months in the therapeuticmalaria group.During the first three years of this investigation the

patients treated with artificial fever received 50 hoursof fever at a rectal temperature of I05 to io6 F. (40.6 to

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4I-I C.), given as ten treatment sessions of five hours each.In the last two years of the study it was found that Xaseries of twelve individual fever sessions of three hourseach (a total of 36 hours of fever) at a rectal temperatureof IO5-8 F. (4I C.) was equally effective and had thedecided advantage of permitting the treatment of agreater number of patients.The extraordinary success of the Colorado investigators

in following the progress of these patients is indicatedby the fact that, with the exception of those who died,all of the malaria-treated cases and two-thirds of thosetreated with artificial fever during the preliminarystudy (reported in I936) were followed during the entirefive-year period. Most of those who disappeared wereknown to have responded favourably to fever-chemo-therapy. The employment of skilled social workers,utilizing a rotating roster, was of great value in inducingpatients to return for progress studies at intervals of sixmonths following the completion of the course of chemo-therapy subsequent to fever therapy.

TABLE II.-DEMENTIA PARALYTICA: TYPES OF TREAT-MENT AND CLINICAL RESULTS DURING FIVE-YEARPERIOD

(Ewalt and Ebaugh, University of Colorado PsychopathicHospital, Denver, Colorado)

Artificial Fever. Therapeutic Malaria.

Clinical Status.Number of Perc Number of entage.Cases. enae Cases. Pecna.

Remission . . . . 25 I9% 7 7%Improved . . . . 68 50% 50 5%

(Remission and Improved) v (93) (69%) (57) 58%)

Unimproved. . . . 3I 22% 27 27%Died within 3 months of treat-ment . . . . 2 Ip4% 5 5%

Died subsequently . . 8 6.6% 9 9%

Total . . . I34 990% 98 99%

The clinical therapeutic results achieved by theColorado workers are summarized in Table II. Of the

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I34 paretic patients receiving artificial fever therapy,25 (19 per cent.) achieved remission, as compared with7 (7 per cent.) of the 98 patients treated with malaria.Sixty-eight (50 per cent.) of those treated with artificialfever and 50 (5I per cent.) of the patients receivingtherapeutic malaria were improved. The criteria usedin determining " remission " and " improvement " werethe same as those adopted by the Committee on Non-Specific Therapy of Syphilis, of the U.S. Public HealthService.

Thus, 69 per cent. of the patients treated with artificialfever were benefited, as compared with 58 per cent. ofthe malaria-treated patients. It is interesting to observethat approximately the same differences existed in thefive-year series as in the one-year series described in thepreliminary report by the same investigators. While theimprovement rate and the relapse rate during the periodsof post-therapy observation were approximately the samein the one-year and five-year studies, the differencesappeared to be due to the better immediate response ofpatients treated with artificial fever. The authorsexpress the belief that this difference may be due to thefact that with artificial fever the patients may be treated-at higher temperature levels than is possible with malariatherapy. Another factor to which significance wasattributed is that patients usually gained weight duringthe course of artificial fever therapy and in most instanceswere in distinctly better physical condition at the con-clusion of the course. The patients treated with malaria,on the other hand, usually lost weight and developedvarying degrees of anaemia despite energetic efforts toprevent these sequele.The results obtained with either form of fever therapy,

grouped according to the degree of severity of the pareticsymptoms, are presented in Table III. As in the co-operative study made by the U.S. Public Health Service,the therapeutic results were best in "mild" paresis(45 per cent. of remissions with artificial fever and25 per cent. with malaria therapy). Among those with" intermediate " symptoms and signs, 23 per cent.obtained remission following artificial fever therapy ascompared with 7 per cent. of those who received thera-peutic malaria. Full remission did not occur in anypatient with " severe " paresis followiing either method

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TABLE III.-DEMENTIA PARALYTICA: CLASSIFICATIONOF CLINICAL GROUPS IN RELATION TO CLINICALRESU1;LTS

(Ewalt and Ebaugh, University of Colorado PsychopathicHospital, Denver, Colorado)

Artificial Fever. Therapeutic Malaria.

Clinical Status. Mild. Intermediate. Severe. Mild. Intermediate. Severe.

No. Per No. Per No. Per No. Per No. Per No. Percent. cent. cent. cent. cent. cent.

Remission . 9 45 i6 23 0 0 3 25 4 7 0 0Improvement. II 55 39 54 i8 41 6 50 35 64 9 29Unimproved . o 0 I2 17 I9 43 I 8 II 20 I5 48Died . . 0 0 3 4 7 i6 2 17 5 9 7 23

Total . 20 Ioo% 70 98% 44 Ioo% 12 Ioo% 55 Ioo% 3I 100%

of fever therapy. The proportions of "improved"patients were essentially the same with either mode oftherapy, except that among the patients with " severe."paresis, 4I per cent. responded favorably to artificialfever therapy as compared with 29 per cent. of thosereceiving therapeutic malaria. Of the patients with" mild " paresis, all were benefited by artificial fevertherapy and only one failed to respond favourably tomalaria therapy.None of those treated with artificial fever died during

the course of fever therapy, while two died during malariatherapy. Two patients (I.4 per cent.) treated withartificial fever died within three months of treatment,as compared with five deaths (5 per cent.) during thisinterval among those treated with malaria. The numberof subsequent deaths was not significantly different(8 patients, or 6*6 per cent., in the artificial fever groupand 9 patients, or 9 per cent., in the therapeutic malariagroup).While marked clinical improvement was maintained

in many individuals with persistently positive spinalfluid serology, there was an appreciably greater propor-tion of serologic reversals from positive to negativeamong those who experienced clinical remission orimprovement. The spinal fluid serologic reactions werereversed to negative in ii per cent. of those treated withartificial fever and in 6*i per cent. of those receiving

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therapeutic malaria. The reactions became less positivein 35 per cent. of those in the artificial fever therapygroup and in 28-5 per cent. of the malaria-treated patients.The serologic reactions remained positive in 35 per cent.of those treated with artificial fever and in 408 per cent.of those who received malaria therapy. Eighteen percent. of the patients who were treated with artificial feverand 24-4 per cent. of those who were treated with malariawere not available for final evaluation of cerebrospinalfluid serology. A large proportion of those who failed toreturn regularly for re-examination were known to haveachieved a successful clinical result. Thus, of theIO9 patients treated with artificial fever who wereavailable for repeated serologic re-examinations, 62 (or57 per cent.) exhibited reversal or improvement in theirserologic status; of the 74 malaria-treated patientssubjected to adequate serologic study, 34 (or 46 per cent.)showed similar degrees of serologic improvement.Ewalt and Ebaugh found that intensive chemotherapy

subsequent to fever therapy is an essential requirementfor sustained optimum results. These authors expressedthe belief that the variations in therapeutic resultsreported from different clinics may well be due in largepart to the degree of effort exerted in inducing patientsto return at regular intervals for chemotherapy and forclinical and serologic re-examinations.

Finally, it is pertinent to observe that Ebaugh andEwalt have now abandoned malaria therapy in favourof artificial fever therapy.

RECENT REPORTS BY BENNETT, et al., UNIVERSITY OFNEBRASKA, OMAHA

The favourable experiences of Professor A. E. Bennettand his associates at the University of Nebraska, Omaha,with artificial fever therapy combined with chemotherapyin the management of the various stages of neurosyphilishave been described in five recent publications (5). Onereport (5c) deals with a review of a five-year experience inthe treatment of dementia paralytica (G.P.I.) by thiscombined method at the University of Nebraska Collegeof Medicine and at the Hastings (Nebraska) State Hospital.The apparatus employed for the production of fever wasthe Kettering hypertherm. Comparisons were made of

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the artificial fever-chemotherapy method with previousexperiences in the use of chemotherapy alone (trypars-amide plus heavy metals) and in the employment ofmalaria inoculation followed by chemotherapy. Thecomparative incidence of remissions resulting from theuse of these therapeutic programs is shown graphicallyin Chart I. It may be observed that the percentage ofparetic patients achieving remission with artificial fevercombined with and- followed by chemotherapy (53 percent.) was significantly greater than that which followedeither malaria inoculation and subsequent chemotherapy(42 per cent.) or chemotherapy alone (I2 per cent.). Thepatients treated with artificial fever received 50 hours offever (rectal temperature) above IO5 F. (40.6 C.), inducedby means of the Kettering hypertherm, usually given inten to fifteen 3 to 5 hour sessions. Chemotherapy duringand subsequent to the fever sessions consisted of injec-tions of o-o6 gram of mapharsen (meta-amino-para-hydroxy-phenylarsine oxide), usually preceded by con-current injections of a bismuth salt (o-oi gram). Themalaria-treated patients received twelve chills, followedby tryparsamide and bismuth therapy, usually for severalyears. Those paretic patients who were treated withchemotherapy alone received adequate courses oftryparsamide and heavy metals (bismuth and mercury).

Particular mention should be made of a special groupof I2 patients who had been committed to the HastingsState Hospital for periods of from one to five yearsbecause of advanced paretic dementia. All had receivedmalaria therapy followed by long courses of tryparsamideand bismuth therapy. None achieved complete remission.The patients in this refractory group were then given acourse of 50 hours of artificial fever combined withauxiliary mapharsen therapy. Four (or 33 per cent.) ofthose patients obtained complete remission, 3 (or 25 percent.) were improved, while the remaining 5 patientswere unaffected. Thus, 58 per cent. of those classed asmalaria-failures were benefited by subsequent artificialfever therapy.

In addition to the 37 (or 53 per cent.) of the 70 patientstreated with artificial fever combined with mapharsentherapy who exhibited remissions, there were 20 addi-tional patients (or 28 per cent.) who were improved.Thus, 8i per cent. of the patients responded favourably.

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The spinal fluid serologic reactions were reversed tonegative in 24 patients (or 34 per cent.), and became lesspositive in 26 (or 37 per cent.).

Bennett and his associates (5a, b, e) have reported simi-larly favorable experiences in the treatment of asympto-matic neurosyphilis, tabes dorsalis, the tabetic form ofdementia paralytica, and meningovascular neurosyphiliswith combined artificial fever and chemotherapy. Of 8patients with asymptomatic neurosyphilis, all of whomhad had long-continued chemotherapy previously, thespinal fluid serologic reactions were reversed to negativein 5 patients, were less positive at the time of the lastobservation in 2 and were unchanged in one uncooperativepatient who had only 29 hours of fever.

All of I2 patients with meningovascular neurosyphilis,of whom 8 had not responded to presumably adequatechemotherapy, were benefited. Four patients had hemi-paretic features; 3 had palsies of the cranial nerves;3 had aphasic, convulsive and confusional psychoticreactions; 3 had chronic headaches associated withincreased intracranial pressure and meningiticphenomena; one had a syndrome simulating multiplesclerosis. Except in the cases of one patient with hemi-plegia, and another with occasional convulsions, all wererid of their symptoms. Prompt and striking improve-ment was observed in the aphasic and meningiticsymptoms. Because of the presence of vascular compli-cations, many of these patients would have been unableto tolerate malaria therapy. The great advantage incontrolling by physical means the height and the durationof the fever was particularly apparent in this group ofpatients.

In 25 patients with tabes dorsalis, the predominantsymptoms were lightning pains and gastric crises inI7 patients, ataxia in 7 patients, and " cord bladder "in 2 patients. The clinical results included completerelief from symptoms in i8 patients (chiefly those withroot pains); some degree of improvement in 5 and noimprovement in 2. One patient experienced recurrenceof root pains; in another the disease progressed todementia paralytica after a long period of apparentimprovement.As a result of these and other studies, the authors drew

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years or in poor physical condition, including those withsuch complications as hypertension or aortitis, can betreated with greater safety with artificial fever becausethe height and duration of fever can be controlled readily ;that the concurrent employment of artificial fever andchemotherapy increases therapeutic effectiveness; thatthe prescribed number of hours of fever are more easilyobtained by physical methods; that the results of treat-ment are definitely correlated with the height and dura-tion of fever; that continuous hospitalization is not arequirement when artificial' fever therapy is used exceptfor those exhibiting severe psychotic manifestations; thatthe relapse rate is lower with physically induced fever;that the mortality rate is less with artificial fever; thata significant proportion of neurosyphilitic patients whofail to respond to malaria therapy or who obtain onlymoderate degrees of improvement following such treat-ment are benefited by subsequent artificial fever therapy;that certain patients who would not be accepted ascandidates for malaria therapy may be benefited byjudiciously applied artificial fever therapy; and thatartificial fever therapy combined with chemotherapy isthe most effective method of therapy now available forresistant asymptomatic neurosyphilis and for all formsof symptomatic neurosyphilis.

REPORT BY BROMBERG, WASHINGTON UNIVERSITY,ST. LOUIS

Bromberg (6) has recently described his successfulexperiences in the treatment of various manifestationsof neurosyphilis with artificial fever therapy (utilizingthe Kettering hypertherm) combined with chemotherapy,during a three-year period. The therapeutic programemployed by Bromberg was essentially similar to thatused by Bennett, et al., and by Ewalt and Ebaugh (vyideut supra).

It is of more than passing import to observe thatBromberg and his skilled associates have treated over300 patients with artificial fever therapy, many of whomwere quite ill, without a single fatality.

Of-76 patients treated by Bromberg for various mani-festations of neurosyphilis, there were 2I with dementiaparalytica, I4 with the tabetic form of dementia paralytica

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(taboparesis), 2I with tabes dorsalis, 8 with meningo-vascular neurosyphilis, and I2 with asymptomatic neuro-syphilis. Eighteen of the 2I paretic patients (or 86 percent.) were improved; 3 were not benefited. Of the14 patients with the tabetic form of dementia paralytica,I2 (or 85 per cent.) were classified as improved. Amongthe 2I patients with tabes dorsalis, i8 (or 86 per cent.)responded favourably; relief of root pains and gain inweight were outstanding features of the clinical responseof the tabetic patients. All of the 8 patients withmeningovascular neurosyphilis experienced prompt andmarked improvement. The spinal fluid serologicresponses were uniformly good in all of the I2 patientstreated for asymptomatic neurosyphilis.

REPORTS BY TRAUTMAN, U.S. PUBLIC HEALTH SERVICE,U.S. MARINE HOSPITAL, NEW ORLEANS

In comprehensive reviews of the experiences in artificialfever therapy during the past six years at the U.S.Marine Hospital, New Orleans, Trautman (7) tells of thetreatment of 985 patients (a total of 5,500 treatmentsessions), with one death. One hundred and nine patientswere treated for neurosyphilis. The apparatus employedwas the Kettering hypertherm. Most of the patients hadreceived routine chemotherapy in the Marine Hospital orelsewhere, with little or no benefit, prior to the institutionof artificial fever therapy. Chemotherapy was employedby Trautman in conjunction with the fever sessions andwas continued after the course of fever treatments wasterminated.Most of the patients admitted to the U.S. Marine

Hospitals are officers and sailors of the merchant marine.Since these men receive free medical care from theU.S. Public Health Service, they must agree to remainunder observation at the discretion of the medicalofficers. Thus, there is provided an exceptional oppor-tunity to study the results of treatment under the morefavourable circumstances of continuous hospitalizationthan is usually possible in general hospitals. The onlydisadvantage is that it is sometimes difficult to obtaindata on the progress of such patients some years after thecourse of treatment. In a high proportion of cases,however, the patients have returned to the U.S. Marine

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Hospital at New Orleans or to some other U.S. MarineHospital for such studies.

Fourteen patients with dementia paralytica received anaverage total of 6o hours of fever, at a rectal temperature

o level of 104-I05 F. (40-040-6 C.). There were 2 patientsr( who exhibited symptoms of "mild" paresis; oneI recovered completely; the other improved clinically but

%J passed from observation. Of 8 patients with " inter-mediate" paresis, 6 obtained remissions and 2 wereimproved. There were 4 patients with " severe " paresis;of these, one showed improvement; in one, the diseaseprogressed; in the other 2, treatments were discontinuedbecause of the severity of the disease and because ofassociated cardiovascular complications. Thus, of the14 paretic patients, io (or 7I per cent.) are known to-havebeen benefited, while the outcome is not known in oneadditional case.Eleven patients with tabes dorsalis received an

average of I3 fever treatment sessions of five hours each,at a rectal temperature of I04-I06 F. (40.0-4I-I C.), at

1*6* intervals of one week. Of 5 patients with " mild"tabetic symptoms, 4 obtained complete symptomaticrelief and the fifth patient was markedly improved. Inone case of " intermediate " tabetic involvement therewas no improvement. The 5 patients with " severe "tabetic symptoms were benefited in that they wererelieved of the associated pains. Hence, I0 (or go percent.) of the ii tabetic patients obtained some degree ofclinical improvement. The spinal fluid serologic reactionswere reversed to negative in 5 patients, and became lesspositive in 2.

There were I3 patients with meningeal, vascular, orcombined meningo-vascular neurosyphilis. Of the 7patients with meningeal involvement, all respondedfavourably; prompt relief of symptoms was usuallyobserved after the first fever session. Three of the4 patients with vascular neurosyphilis had completesymptomatic recovery, while the fourth had sufficientimprovement to enable him to undertake light work.The 2 patients with meningo-vascular neurosyphilis weremoderately improved. The spinal fluid reactions becamenegative in 7 of the I3 patients and were less positive atthe time of last observation in 2 ; the serologic outcomein 2 patients is not known, The prompt response as

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regards the disappearance of the meningitis symptoms andthe restoration of the spinal fluid cell count and globulincontent to normal levels were the outstanding features inthis group. All were benefited by the treatment.

Seventy-one patients with asymptomatic neurosyphiliswere treated by Trautman and his associates. Of the45 patients in this group on whom adequate post-therapyobservations were made, the spinal fluid serologicreactions were reversed to negative in 30 (or 66 and two-thirds per cent.), while the remaining I5 retained somedegree of serologic positivity. The blood serologicreactions became negative in 29. It is probable that thepercentage of serologic reversals would have been greaterif some of the patients had been observed over longerperiods. None of the 45 patients, the outcome of whosetreatment is known, has developed any evidence ofclinical neurosyphilis.

RECENT REPORT OF NEYMANN, NORTHWESTERNUNIVERSITY, CHICAGO

To his many previous reports, Neymann (8) has contri-buted a recent summation of his experiences in theartificial fever therapy of syphilis since I927. Neymannand his associates (Osborne, Koenig, Feinberg andMarkson) have utilized electropyrexia (short wave dia-thermy currents, now applied in an air-conditionedcabinet) combined with chemotherapy (tryparsamide plusbismuth or mercury) in the treatment of I20 patients withdementia paralytica. Fifty-five (or 46 per cent.) achievedcomplete remission. In determining remission, Neymannincluded only those paretic patients who were not onlyrid of their symptoms, but who had also resumed'theirformer or equivalent occupations and who had remainedat work for at least six months. Twenty additionalpatients (or I7 per cent.) were improved. Thus, a totalof 75 patients with dementia paralytica (or 63 per cent.)were benefited.

In a survey based upon the clinical results reported bysome fifty investigators in the treatment with artificialfever of 975 patients with dementia paralytica, producedby a variety of physical methods, Neymann found thatat least 266 (or 27 per cent.) had obtained remission,while 354 (or 36 per cent.) were improved. The recorded

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percentage of remissions is probably lower than the actualproportion, since Neymann included in this category onlythose patients in whom there was unequivocal evidenceof remission. In sum, 620 of the 975 paretic patients(or 63 per cent.) were benefited by artificial fever therapy.In comparing these results with those attained withmalaria therapy, Neymann stated that the use of artificialfever therapy increased the total rate of improvement inpatients with dementia paralytica by 2I per cent., anddecreased the treatment-death rate to an almost negligiblelevel.

In a similar analysis of the reported clinical resultsobtained by I7 investigators utilizing several differentphysical modalities for the production of artificial fever inthe management of tabes dorsalis, Neymann found thatof 114 tabetics, 75 (or 66 per cent.) were improved. Inhis own series of 8 tabetics, all of whom improved, thedisappearance of root pains was the outstanding featureof therapy. Tabetic crises and pains did not recur duringperiods of post-therapy observation extending from oneto three or more years.

After I3 years of experience with artificial fevertherapy and after extensive previous experience withmalaria therapy, Neymann has come to regard the" mythical, unproved and much extolled magical actionof the plasmodium of malaria" in the treatment ofneurosyphilis as a " fetish or taboo in the minds of itsmost ardent advocates."

REPORTS BY HINSIE AND BLALOC K, NEW YORK STATEPSYCHIATRIC INSTITUTE AND HOSPITAL, NEW YORKIn addition to providing further evidence of the merits

of artificial fever therapy, the reports by Hinsie andBlalock are of particular significance in that a carefulanalysis was made of the results obtained with artificialfever therapy alone, with artificial fever therapy followedby a course of I2 or more injections of tryparsamide andbismuth, and with artificial fever therapy combined withan injection of tryparsamide just prior to each fevertreatment and followed by a course of tryparsamide afterthe conclusion of the course of combined fever-trypars-amide treatments. The apparatus employed by Hinsieand Blalock was the ultra high-frequency' apparatus

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developed by Whitney, known as the " radiotherm."The data are based on a study of I46 adult patients withacquired dementia paralytica observed during a period offive and one-half years. The patients in each groupreceived ten treatments at approximately I05 F. or(40.6 C.), each of seven hours' duration, on alternate daysfor the purpose of simulating the malarial character ofthe febrile course. At the end of the second year of post-therapy observation, the remission rate in the patientswho received artificial fever therapy alone was i8 percent.; in those who received an equivalent amount offever therapy followed by a course of tryparsamidetherapy, the remission rate was 27 per cent.; in thosereceiving injections of tryparsamide in conjunction withand following fever therapy the remission rate was30 per cent. An additional 29 per cent. were improvedfollowing fever therapy alone, while the percentages ofimprovement in the other two groups were 36 and 35.On-the basis of these and other studies, Hinsie and Blalockexpressed the beliefs that the employment of fevertherapy alone produced results comparable to thoseobtained with malaria therapy and that much morefavourable results are obtained when chemotherapy isemployed in conjunction with artificial fever therapy.

In a recent communication (I938), Hinsie and Blalockhave reported the serologic results of both blood andspinal fluid of patients treated for dementia paralyticawith either malaria therapy or artificial fever therapy.The results are based on observations made in the samehospital during a four-year period. At the end of thefourth year, the blood serologic reactions were reversedto negative in 28 per cent. of the malaria-treated patientsand in 59-I per cent. of the patients treated with artificialfever; the spinal fluid reactions became negative in57-2 per cent. of those treated with malaria and in63-6 per cent. of those who received artificial fevertherapy. These workers also observed that while serologicimprovement is in general independent of the clinicalresponse to either malaria or artificial fever therapyduring the first few years after therapy, a persistentlypositive serologic ensemble after the third or fourthyear following fever therapy has considerable prognosticsignificance since it is much more frequently associatedwith an unfavourable clinical outcome.

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In common with other investigators who have hadextensive experience in the use of artificial fever therapy,Hinsie and Blalock have found no evidence that therelapse rate of paretic patients is higher with artificialfever therapy than with malaria therapy.

PERSONAL EXPERIENCES IN THE TREATMENT OFNEUROSYPHILIS

The history and progress of our work in artificial fevertherapy since its inception in I93I has been recorded inseveral publications (io). Impressed by the successfulclinical results attained early in the course of the under-taking, despite the handicap of the inefficient physicalmodalities then available, we decided that futureresearches should be directed along two separate butrelated routes, namely, toward the. development ofsimpler, safer and more easily controllable apparatus forthe production of fever, and towards an explorationof the possible fields of usefulness for this mode -oftherapy.

After some years of experimentation with suchmodalities as hot'baths, hot air cabinets, electric blankets,diathermy electrical currents and ultra high frequencyelectrical currents (radiotherm) we, with the indispensablecollaboration of Dr. Charles F. Kettering and of Mr.Edwin C. Sittler, ultimately devised an air-conditionedapparatus which fulfilled the requirements at which wehad aimed. Eighty of these units were lent to 26 researchcentres for the purpose of widening the scope of theinvestigation. The physicians and nurses charged withthe responsibility of administering the treatments pro-perly in the various collaborating institutions receivedspecial training from us before the apparatus was releasedfor their use.Because the demands from other institutions exceeded

our ability to supply them with this apparatus, an agree-ment was made with a reliable manufacturer of physicaltherapy apparatus (Liebel-Flarsheim Company, Cincin-nati, Ohio) to manufacture the apparatus now known asthe " Hypertherm" (Fig. i), under license of. patentsheld by Dr. Kettering and the General Motors Corpora-tion, without profit either to Dr. Kettering or to theGeneral Motors Corporation. This apparatus is sold at

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a reasonable cost only to qualified institutions (not toprivate practitioners) with the stated provision that thephysicians and nurses who are to engage in the workmust receive adequate preliminary training at an ap-proved institution. During the past two and one-halfyears one or more hypertherms have been installed inqualified hospitals in the United States at the rate of oneinstallation per Week. Scores of other hospitals in this

111I'..>: I

FIG. I. The Hypertherm.

country and abroad have installed other types of equip-ment for artificial fever therapy.

Coincident with the early engineering developmentsrelated to the apparatus, it was natural that the firstclinical applications should be directed towards adetermination of the possible usefulness of artificial fevertherapy in the management of dementia paralytica.Wagner-Jauregg's successes with the treatment of thisdisease with malaria therapy had been widely con-firmed. Comparable clinical results had also beenobtained in those cases of dementia paralytica in whichsustained high fever occurred following inoculations with

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the organisms of rat-bite fever and of relapsing fever,or following injections of vaccines prepared from typhoidand paratyphoid organisms or from Hcemophilus ducreyi,or of heteroproteins such as milk or peptone, or ofchemical substances such as sulphur. The early claimsfor specific, intrinsic merit in malaria inoculata appearedno longer to be tenable. Since the common denominatorof this wide variety of agencies was the production offever, many investigators (Neymann, Osborne, Bierman,Schamberg, Bessemans, Whitney, Carpenter, Warren,Kettering, the authors and others) were stimulated tosearch for safer and more easily controlled physicalmethods for accomplishing the same purpose.

Hence, the first patients treated by us with artificialfever, produced by means of various physical modalities,were those who were suffering from dementia paralytica.Despite the difficulties and discouragements encounteredin the quest for suitable physical methods, it was observedfrom the start that the clinical results were at leastcomparable to those previously obtained by us and byothers with malaria therapy.

Since the experiences of many workers with malariatherapy provided unmistakable evidence of theadvantages of combining chemotherapy with malariatherapy, and since our results in a small group of patientstreated with fever therapy alone were distinctly inferiorwe have utilized the combined fever-chemotherapymethod practically from the outset.

- One advantage of the artificial fever method in con-tract to malaria therapy is that arsenic and bismuthcompounds may be administered with each fever treat-ment. Our observation (II) that fever appeared to exerta protective function against anaphylactic phenomenaproduced in sensitized individuals by arsenic, led us tochange from the practice of injecting the arsenicalcompound half an hour before each fever treatment wasbegun to that of making the injection when the rectaltemperature first reached the level of I05 F. (40.6 C.)this was ordinarily about 75 to go minutes after the feversession was started. By this procedure it is possibleto abolish or to minimise greatly arsenical reactions inpatients known to be highly sensitized to this substance.

For purposes of comparison, a variety of arsenicalcompounds has been employed (bismuth arsphenamine

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sulfonate (bismarsen), tryparsamide, neoarsphenamine,or meta - amino - parahydroxy - phenylarsine oxide(mapharsen) ). One significant observation has accruedfrom this comparative study, namely, that regardless ofthe type of arsenical compound used, and despite thegreat variation in arsenic content, the time required forclinical remission and for serologic reversal did not varyappreciably. Factors other than quantitative arseniccontent appear to operate in producing a favorableoutcome. During the past four years (since February,1937), we have utilized mapharsen (usually in individualdoses of o-o6 grams) to the exclusion of other arsenicalcompounds. Our experiences confirm those of the manyinvestigators who have found mapharsen to be lesstoxic than most other available compounds and to pro-duce at the least equal clinical and serologic responses.

Just before each fever treatment was commenced thepatient received an intramuscular injection of 4 grains ofbismuth salicylate.During the first six years of this investigation, the usual

course of treatment for neurosyphilitic patients consistedof I0 five-hour sessions of artificial fever therapy atI05-I06 F. (40.6-4ii C.), with an optimum level ofI05 8 F. (4I C.), usually at weekly intervals, for a total offifty hours. This more or less arbitrary selection ofheight and duration of fever was based upon an analysisof the results which had been obtained with malariatherapy, which revealed that the proportion of remis-sions was greatest in those paretic patients who experi-enced approximately this amount of fever followingmalaria inoculation.

After the course -of combined bismuth-arsenic-fevertherapy was completed, the patients received an addi-tional course of bismuth and arsenic injections, givenconcurrently, at weekly intervals for a period of 20 weeks.The observation that most paretic patients appeared

to experience maximum improvement after the first fiveor six five-hour fever sessions led us, in I937, to experi-ment with a reduction in the total number of hours offever together with a decrease in the number of hours pertreatment. A comparison of clinical and serologicresponses by both procedures revealed no essentialdifferences. Consequently, the usual course of fevertherapy during the past four years has consisted of

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twelve three-hour sessions at an average temperaturelevel of I05*8 F. (4I C.), or a total of 36 hours of fevertherapy at this level. Furthermore, it has been foundadvantageous and equally efficacious to administer fevertherapy at more frequent intervals. Thus, patientsfrom distant cities who cannot commute at weeklyintervals, were usually hospitalized and received threefever treatments during each week for four weeks. Nodifficulties have arisen from this program, either as aresult of shortening the interval between treatments orfrom the more frequent administration of chemotherapy.Most of the patients were from Dayton or the immediatevicinity. Practically all of the local patients weretreated on an ambulatory basis at semi-weekly or weeklyintervals. The only exceptions were those who requiredcontinuous hospitalization during the course of treatmentbecause of physical or mental complications. Theadvantages of this latter program of shorter sessions atmore frequent intervals are that it is possible for onenurse-technician to treat two patients each day, it reducesthe cost of the treatments, and it furthers the programof ambulatory care.

Individualization of the therapeutic program accord-ing to the status of the patient under treatment is ofparamount importance. Most patients being-treated forneurosyphilis can tolerate three hours of fever at I05-io6 F. (40.6-4ii C.) with no difficulty. Markedlydebilitated patients, those in the upper age-brackets andthose with manifestations of mental deterioration con-stitute a group which ordinarily would be. considered tobe poor risks for either malaria or artificial fever therapy.It has been our practice to administer artificial fever tosuch patients in shorter sessions at a lower temperaturelevel in the beginning, increasing the height and lengthof fever as the course of treatment progresses. In thismanner we have been able with minimal risk to afford alarge group of patients the benefits of a course of artificialfever therapy combined with chemotherapy. By suchindividualization it has been possible to extend treatmentto advanced tabetic patients and to deteriorated pareticpatients in whom ordinarily little is to be expected in theway of clinical improvement. The results have fullyjustified the additional effort. For the first treatmentthey are subjected to one hour of fever at I02-I03 F.

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(38.8-39.4 C.). If this is well tolerated, the next treatmentwhether weekly or semi-weekly, is given for one hour atI03-I04 F. (39.4-40.0 C.). The fever is increasedduring the next treatment to I04-IO5' F. (40.o-40o6 C.)and finally to I05-I06 F. (40 6-41I. C.). When thedesired height is reached, the length of the fever sessionis gradually increased until we are able to give threehours of fever at I05-I06 F. (40.6-4ii C.). If at anytime the patient should display evidence of intolerance tothe treatment, either the same length and height of feveror a shorter session at a lower temperature level is givenat the next treatment. The average patient is usuallyable to tolerate the full three-hour session at I05-Io6 F.(40o6-4I-I C.) after three or four of the short sessions atlower levels. This individualization has been renderedmore feasible by the improvements in apparatus and intechnic.

Since I93I, we have subjected II39 patients to arti-ficial fever therapy. Of this number, 376 patients havebeen treated for various manifestations of syphilis.* Withone possible exception, no patient was harmed by thetreatments save for the occasional occurrence of mildskin burns during the early phase of the work. With theimprovements in the apparatus this hazard has beenentirely eliminated. We have not observed a singleinstance of skin burn during the course of artificial fevertreatments for over four years. Even erythema of theskin no longer occurs.The single exceptional case in which death occurred

was that of a 37 year-old man, who was suffering fromfulminating meningovascular syphilis and rapidly pro-gressing blindness due to optic atrophy. He had hadhypertension for an undetermined period and the historysuggested well-advanced cerebral vascular sclerosis. Atthe insistence of the patient and his physicians and withfull recognition on the part of all concerned as to theunusual gravity of the situation, the patient was givencautiously a single fever treatment of four hours' duration.At the conclusion of the treatment his general conditionwas good. Seven hours later it was noted that he wassomewhat confused and that there was beginning

* Most of the remaining patients were treated for gonococcic infection, certainforms of infectious arthritis, Sydenham's chorea, rheumatic fever, non-specificocular infections, or undulant fever.

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paralysis of the right extremities. By the next morningthe hemiparesis was complete and the patient lapsed intounconsciousness. He died the second day after thefever treatment, probably as the result of cerebralhaemorrhage. Permission for post-mortem examinationwas denied.

Only those patients who have been under observationfor periods of from i8 months to 9 years and 4 monthsare considered in this report. Furthermore, the results oftherapy as stated in this report refer only to the responsesattained after a single course of combined artificial feverand chemotherapy. Those patients who did not improvefollowing the usual course, but who attained varyingdegrees of improvement following a second course, willbe considered separately.The records of 75 syphilitic patients, or 20 per cent. of

the total number of those treated for this disease, areincomplete as a result of the failure of these patients toreturn at regular intervals for clinical and serologicre-examinations for at least two years following the courseof therapy. It is known that many of these personswere benefited, at least for periods of several months, bythe course of treatment. Many of those who obtainedimprovement failed to return, despite the urgent pleas ofphysicians and social workers, because they could not beconvinced that it was necessary. A majority of thepatients have been observed at regular intervals for overfour years.Of 208 patients treated by us for neurosyphilis, the

records of 43 or (20.6 per cent.) were excluded fromconsideration because of incomplete post-tlferapy observa-tion. Thus, the records of i65 neurosyphilitic patientsfulfil the necessarily rigid criteria for critical analysis.These include 65 patients with dementia paralytica, 27with the tabetic form of dementia paralytica (taboparesis),29 with tabes dorsalis, 6 with meningeal neurosyphilis,ii with vascular neurosyphilis, 9 with meningo-vascularneurosyphilis and i8 with asymptomatic neurosyphilis(Table IV).

(a) Dementia ParalyticaThe 65 patients treated for dementia paralytica were

grouped according to the classification (described pre-viously) adopted by the Committee on Non-Specific

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FEVER THERAPY

Therapy of Syphilis of the U.S. Public Health Service,as " mild," " intermediate," or " severe." Similarly, inthe appraisal of the results of therapy, the criteria adoptedby this Committee were employed. The median age ofpatients treated for dementia paralytica was 37-8 years.All but I5 of the 65 paretic patients had received pre-sumably adequate chemotherapy prior to the institutionof artificial fever therapy; the others had receivedinsignificant amounts of chemotherapy or none.

Included for analysis were the clinical and serologicdata on 22 patients with " mild " dementia paralytica.Further proof of the necessity for treating paretic patientsduring this early stage of the disease is found in the factthat 2I of the 22 patients (or 95 per cent.) achieved-remission; one patient was not improved. In thosetreated for " mild " paresis, the blood serologic reactionswere reversed to negative in I3 patients (or 59 per cent.),became less positive in 8 additional patients (or 36 percent.), and were not influenced in i patient (or 5 percent.). The spinal fluid serologic reactions becamenegative in I3 patients (or 59 per cent.), were less positiveat the time of last observation in 7 patients (or 32 percent.), and remained positive in 2 patients (or 9 percent.).Of the 29 patients with " intermediate " dementia

paralytica, 2I (or 72 per cent.) obtained remission, twopatients (or 6 per cent.) were improved. Thus, 78 percent. of those with " intermediate' paresis were benefited.Three patients in this group were not improved, and thedisease progressed following treatment in 3 additionalpatients. The blood serologic reactions were reversedto negative in 5 patients (or I7 per cent.) of those with" intermediate " paresis, became less positive in 23patients (or 79 per cent.), and remained positive inI patient (or 4 per cent.). The spinal fluid serologicreactions were changed to negative in 5 patients (orI7 per cent.), were less positive at the time of the lastre-examination in 2I patients (or 73 per cent.), andremained positive in 3 patients (or IO per cent.).As would be anticipated, the proportion of favourable

clinical responses to the combined method of fever-chemotherapy was distinctly less in the patients with" severeY" paresis. Thus, of I4 patients in this advancedstage of the disease, only 2 (or I4 per cent.) achieved

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clinical remission. Six additional patients (or 43 percent.) were improved. In 3 patients there was noimprovement, while in 3 others the disease progresseddespite treatment. It is perhaps of importance toindicate, however, that even in patients with manifesta-tions of advanced paresis considerable salvage waseffected. Over one-half of the patients in this categorywere benefited. The responses of the blood and spinalfluid reactions exhibited no constant relationship to theclinical outcome. The reactions remained strongly posi-tive in some who achieved clinical remission, and werereversed to negative in some in whom the disease processwas either uninfluenced or progressed. The serologicreactions of the blood became negative in 3 patients(or 21 per cent.), became less positive in 6 patients(or 43 per cent.), and remained positive in 5 (or 36 percent.). The spinal fluid serologic reactions were reversedto negative in 2 patients (or I4 per cent.), became lesspositive in 7 patients (or 50 per cent.), and were stillpositive at the time of the last observation in 5 patients(or 36 per cent.).

(b) Tabetic Form of Dementia Paralytica (Taboparesis)In the group of 27 patients with the tabetic form of

dementia paralytica (taboparesis) the symptoms andsigns of paresis usually dominated the clinical picture.All but one had received varying amounts of chemo-therapy prior to artificial fever therapy. While many ofthese patients achieved coincidental improvement inboth tabetic and paretic manifestations, the clinical out-come of therapy was largely dependent upon the relativemildness or severity of the paretic symptoms. Since itwas not considered feasible to classify such patients in"mild," " intermediate " or " severe " categories becauseof the great variation in the relative degrees of pareticand tabetic symptoms, they are considered as one group.The prompt relief of lightning pains and gastric criseswas the outstanding feature of the response to treatment;3 patients experienced recurrence of root pains whichyielded to additional fever-chemotherapy. Those withataxia of short duration usually experienced someimprovement in gait. Three patients with "cordbladder" regained control of bladder function; one

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advanced taboparetic with " cord bladder " was notbenefited.

Seventeen of the 27 taboparetic patients (or 63 percent.) achieved clinical remission of both tabetic andparetic symptoms. Three additional patients (or II percent.) were improved. Thus, 20 of the 27 patients (or74 per cent.) in this group responded favourably. Fivepatients with severe paretic symptoms were not improvedand the disease progressed during and after treatmentin two demented patients, who died six months and oneyear, respectively, after the course of treatment wascompleted.The blood serologic reactions were reversed to negative

in IO patients (or 37 per cent.), became less positive inii patients (or 4I per cent.), and were not influenced in6 patients (or 22 per cent.). The spinal fluid serologicreactions were reversed to negative in IO patients (37 percent.), became less positive in IO patients (37 per cent.),and remained unchanged in 7 patients (or. 26 per cent.).

(c) Tabes DorsalisAll of the 29 patients with tabes dorsalis had received

varying amounts of chemotherapy before artificial fevertherapy was begun. Included in this group of patientswere 4 with " mild " tabetic manifestations,* such aslightning pains of recent origin, paresthesias, pupillarydisturbances, reduced or exaggerated reflexes, or diplopia.There were i6 patients with " intermediates" tabesdorsalis, in which group were included those manifestingsuch signs and symptoms as those mentioned above,together with such additional evidences as " cordbladder," early and mild ataxia, gastric crises, or earlyoptic atrophy. The 9 patients with "severe " tabesdorsalis exhibited such manifestations as marked ataxia,severe lightning pains or gastro-intestinal crises or both,incoordination, "cord bladder," marked hyperesthesiasor paresthesias, optic atrophy, or Charcot joints. Mostof the patients with " severe " tabes dorsalis presentedthemselves with evidences of advanced malnutrition andavitaminosis; many verged on starvation because ofalmost uninterrupted gastro-intestinal crises. These

* Classification of Committee on Non-Specific Therapy of U.S. Public HealthService.

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patients presented the most trying treatment problems.Most would not have been considered as candidates foreither malaria therapy or artificial fever therapy a fewyears ago. With the improvements in the apparatusfor the production of fever and in the technic of adminis-tering the treatments, a significant proportion of thesepatients may be helped, particularly as regards relief fromthe lightning pains or from the gastro-intestinal crises.Such patients are first given short trial fever treatments,at a low fever level, following three or four of which it isusually possible to give the usual three-hour sessionsat I05-8 F. (4I C.). Correction of dietary deficiencies,of anaemia, and often of narcotic addiction, are essentialrequirements in the therapeutic program.

It is unfortunate that the use of fever therapy is stilltoo often regarded as a final, resortive method of treat-ment. Much better results will be achieved when it ismore generally recognized that fever therapy combinedwith chemotherapy is the primary treatment of choicein all types of symptomatic and asymptomatic neuro-syphilis. This fact is particularly apparent in themanagement of patients with tabes dorsalis.

Of the 4 patients with " mild " tabes dorsalis, allobtained prompt and lasting remission. The lightningpains or gastro-intestinal crises, or both, often respondedafter the first two or three treatments. There has beenno recurrence of such pains in the patients with " mild "tabetic symptoms; additional treatments were notrequired in this group of patients. The blood serologicreactions of the " mild " tabetic patients were reversedto negative in 3 patients (or 75 per cent.) and in the fourthpatient (or 25 per cent.) became less positive. The spinalfluid serologic reactions became negative in two patients(or 50 per cent.), were less positive at the time of the lastre-examination in i patient (or 25 per cent.), and remainedunchanged in i patient (or 25 per cent.).Nine (or 56 per cent.) of the i6 patients with " inter-

mediate" tabes dorsalis obtained clinical remissionfollowing one course of combined fever-chemotherapy.The most striking result of treatment was the prompt andpersistent disappearance of the lancinating pains andgastro-intestinal crises. Three patients with mild andearly ataxia were restored to normal gait. Four (or 25per cent.) of the patients with " intermediate " tabes

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dorsalis obtained improvement. Three of these patientsexperienced recurrence of root pains, which were con-trolled with additional fever-chemotherapy. Twopatients with " cord bladder" regained normal controlof bladder function. Some improvement in gait dis-turbance occurred in all of the patients in this group.Three patients (or I9 per cent.) with " intermediate "tabes dorsalis were not benefited by the course of treat-ment. The blood serologic reactions were reversed tonegative in 8 (or 50 per cent.) of the patients with"intermediate " tabes dorsalis, became less positive in4 patients (or 25 per cent.) and were uninfluenced in4 patients (or 25 per cent.). The spinal fluid serologicreactions were reversed to negative in 8 patients (or50 per cent.), became less positive in 2 patients (or I225 percent.), and were unchanged in 6 patients (or 37.5 percent.).The results of treatment were decidedly inferior in the

group of 9 patients with " severe " tabes dorsalis.Remission occurred in only 2 patients (or 22 per cent.).Some measure of improvement, including relief of painsor improvement in bladder function, occurred in 4 patients(or 22 per cent.). In one patient there was no improve-ment. In 2 advanced tabetic patients the disease pro-gressed despite treatment and these patients died of thedisease several months after the completion of the courseof treatment. The blood serologic reactions becamenegative in 4 patients (or 45 per cent.), became lesspositive in 3 patients (or 33 per cent.), and were unchangedin 2 patients (or 22 per cent.). The spinal fluid serologicreactions were reversed to negative in 5 patients (or 56per cent.), were less positive at the time of the last re-examination in 2 patients (or 22 per cent.), and remainedunchanged in 2 patients (or 22 per cent.).

(d) Meningeal NeurosyphilisSix patients with meningeal neurosyphilis were treated

with combined artificial fever therapy and chemotherapy.All but one had had presumably adequate chemotherapy.The characteristic manifestations of syphilitic meningitiswere pr

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