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Journal of Experimental Medicine

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A D E M O N S T R A T I O N OF T R E P O N E M A P A L L I D U M IN
T H E B R A I N IN C A S E S OF G E N E R A L P A R A L Y S I S . *BY H I D E Y O N O G U C H I , M.D., AND J. W. M O O R E , M.D.

(From the Laboratories of The Rockefeller Institute for Medical Research,and the Central Islip State Hospital, New York.)
PLATE 5° .

In the present communication we wish to report the results ofexaminations for Treponema pallidum on seventy paretic brains.
One of us (Noguchi) succeeded in finding the pallidum in twelveout of the seventy specimens?
The relationship of paresis to syphilis has, for years, been oneof the foremost topics of medical interest, especially to psychiatrists.
Since 1857 when attention was first called 2 to the frequency ofsyphilis in the history of patients with paresis, the etiological importance of the former disease has steadily gained recognition, until
now probably the majority of writers agree with Kraepelin 3 that
" W e can to-day declare with the greatest certainty that syphilitic
infection is an essential for the later appearance of paresis." Many,
however, including a man of such enormous experience as Nonne,
still refuse to concede that syphilis is more than an extremely common causative factor. Nonne 4 says, " A t the outset I desire to
make it clear that progressive paralysis is not a specific syphilitic
disease of the brain."Among those who hold "without syphilis, no paresis," there aresome who contend that paresis is nothing more nor less than aparticular form of tertiary syphilis. Kraepelin objects to this view
* Received for publication, January II, 1913.
1 The findings were confirmed later by Dr. Moore as well as by others, amongwhom we may mention Dr. Flexner and Dr. Dunlap. We take pleasure in
expressing our gratitude to Dr. G. A. Smith, Superintendent of the Centra! Islip
State Hospital, for the material studied.
Esmarch, F., und Jessen, W., AUg. Ztschr. f. Psychiat., 1857, xiv, 20.
3 Kraepelin, E., Psychiatrie, Leipzig, 19o4, ii.
* Nonne, M., Syphilis und Nervensystem, Berlin, I9O2.

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on two principal grounds,--the distinctly greater interval between
syphilitic infection and paresis as compared with that in cerebral
syphilis and the refractoriness of paresis to antisyphilitic treatment
This author, however, in commenting on the hitherto vain attempts
to find Treponema pallidum in the tissues and body fluids of paresis,
remarks, " T h i s does not mean that the spiroch~eta is never present
in the body of the paretic. It may have assumed forms so far
unknown to us or have located in places where it has not yet beensought or where it is hard to find."
Of late years a few cases have been reported in which the findings of paresis occurred along with those of cerebral syphilis.
Str/iussler 5 has recently added two cases of this combination toseveral he had already reported. Ranke n and others have demonstrated Spirochceta pallida in the pia and vessel sheaths in congenitally syphilitic brains. In this country Dunlap, of the New
York State Psychiatric Institute, has also shown the organisms in acase of cerebral syphilis. Dunlap has long been of the opinion that,
although tertiary syphilis of the brain and general paralysis arequite distinct and seldom, if ever, occur together, they are but
different manifestations of the same process.
The failure up to the present time to discover Treponema pallidum in the affected nervous system has doubtless added to thegeneral conception that paresis, although of syphilitic origin, canexist without the pallidum playing an active part in the progressiveprocesses. This assumption is valid, of course, only when we grantthat Treponema pallidum can infallibly be demonstrated by themicroscopical techniques hitherto employed. But, as will be seenpresently, this is far from being the case. Besides, the individualexperience on the part of the examiner has much to do with whether
the organisms are viewed or remain undetected, especially in a tissue
in which so many tortuous fibers are present as in the brain.
These facts, coupled with the very significant serological similarities between syphilis and paresis, and the fact that the trypanosome
Str/iussler, Ztschr. f. d. ges. Neurol. u. Psychiat., Orig., 1912 , xii, 365.
6 R a n k e , Ztschr. f. d. Erforsch. u. Behandl. d. jugendl. Schwachsinns, 19o9,ii, 32, 81, 2I I.

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Demonstration of Treponema pallidum in the Brain.

can be found in the brain in sleeping-sickness,--a disease in many
respects similar to paresis,--led the writers to believe that further
search for the syphilitic organism, either in granular or in spiroch~etal form, 7 in paresis was warranted. To this end, tissues weretaken from seventy paretic brains in the possession of the pathological service of the Central Islip State Hospital and stained with
the Levaditi silver method modified in certain respects to produce
an elective stain for the pallidum. The specimens in most of thecases were taken from the first right frontal gyrus; in some, fromthe left hemisphere or gyrus rectus.
The syphilitic organisms were found in twelve cases which wereexamples of undoubted general paralysis. The cases in which thepallida were found showed the classical physical signs. The postmortem findings in the brain in every case were definitely those ofgeneral paralysis. Ten were men and two were women. Seven
were of the cerebral type, and five of the tabetic. In several instances the patients had been picked up on the street in a confused state and had no idea of the duration of the condition.
In the seven cases in which the onset could be satisfactorily determined, the average duration was seventeen months, the longest
thirty months, and the shortest five months. The majority weremuch below the average duration, as estimated by various authors,which varies from twenty-four to thirty-two months. It is possible,then, that we are more apt to find the spirochaeta in those cases
which run a fairly rapid course. The age varied from thirtythree to sixty years, with an average of forty-four years. Brief
abstracts of the case records follow.
J. C. (Io3), age fifty years; duration of disease unknown. He was committed from the workhouse. T h e r e was much confusion; he was disoriented
and his memory was extremely poor. The knee-jerks were unequal and exaggerated; the pupils sluggish and unequal. His speech was distorted, and therewere marked tremors.
Convulsions occurred.
Death occurred after sevenmonths in the hospital.
C. M. (io6), age thirty-nine years; duration unknown, but probably aboutfour months. Syphilis ten years previously. W h e n he was admitted he wasdepressed and apprehensive; he had hallucinations of h e a r i n g ; he was disoriented, and his memory was very poor, with spells of marked confusion. The
Noguchi, H., Jour. Am. Med. Assn., I912 , lix, I236.

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knee-jerks were normal, the pupils sluggish. There were ataxia, distorted
speech, coarse tremors, and convulsions. He died after eleven months in thehospital.
F. B. ( I I 3 ) , age thirty-six years; duration before admission, fourteen months.
Syphilis was denied. On admission he was dull, silly, mildly restless, and had
occasional hallucinations.
His memory showed marked discrepancies. Theknee-jerks were absent, and the pupils slow to light and unequal. His speech
was distorted, and he had convulsions. Later he developed a silly elation anddeteriorated progressively. Death o c c u r r e d ' a f t e r fourteen months in the hospital. The total duration of the disease was thirty months.
S. V. ( I 3 I ) , colored, age thirty-seven years; the duration of the disease
before admission is unknown. Syphilis eight years previously. He was euphoric,his memory was very poor, and he was disoriented. The knee-jerks were muchdiminished, the pupils slightly slow, his speech ataxic, and there were coarse
tremors. Later he developed typical expansive ideas and became very ataxic.
Death occurred after twenty-seven months in the hospital.
J. D. (I38), age thirty-three years; duration before admission, five months.
He was admitted in an hallucinatory depression with nihilistic ideas and a historyof a probable attempt at suicide. A complete mental status was impossible.
The knee-jerks were exaggerated ; pupils unequal, Argyll-Robertson sign present ;there were marked tremors. The spinal fluid showed marked lymphocytosis.
Death occurred after ten months in the hospital.
F. M. (I59), age fifty-five years; duration of disease unknown. He waspicked up on the street in a confused condition. He had absurd hypochondriacal
ideas; " his insides were falling out," etc. He was disoriented and his memory
was very poor. The knee-jerks were exaggerated, and the pupils sluggish.
There were marked tremors, unsteadiness, and Romberg's sign. His speech was
not seriously affected. Depression continued, and he insisted that he could notbreathe or urinate, and that parts of him were dead. He died after four months
in the hospital. The spinal fluid showed positive lymphocytosis and a positive
W:assermann-Noguchi reaction.
E. W. (I7o), age forty-four years; duration unknown. He had had syphilis.
The psychosis was a simple deterioration with marked confusion and disorientation but no delusions. He was silly, his memory was poor, and there were occasional attacks of excitement. T h e k n e e - j e r k s were diminished, and the pupils
slightly slow. The speech showed extreme ataxia. Romberg's sign was present,and tremors were prominent. There were frequent convulsions. Death occurred after two months in the hospital.
E. R. (23o), age forty-eight years; duration unknown. When admitted she
was much demented, confused, completely disoriented, and her memory waspoor. Her mood was one of silly elation. The knee-jerks were exaggerated, thepupillary reaction slow and of narrow range. There was marked distortion ofspeech and writing. There were coarse tremors and increasing ataxia. The
spinal fluid showed marked pleocytosis. Death occurred after six months in thehospital.

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Demonstration of Treponema pallidum in the Brain.

M. M. (235), age forty-two years; duration uncertain. She had been blina
from optic atrophy for two years before admission and had experienced occasional visual hallucinations, but definite mental symptoms seem to have begun
only a few weeks before commitment, when she began to show a change ofdisposition and became forgetful. Syphilis probably occurred twenty years
previously. Her husband was a paretic. On admission she was excited, resisting,and obscene. She seemed clear and gave correct answers in the orientation test
but her memory showed marked discrepancies in time relations. The knee-jerks
were absent, the pupils rigid, her speech drawling and distorted, no tremors, andonly slight ataxia. The spinal fluid showed extreme lymphocytosis. She quieted
down, and during the next two years showed a gradual deterioration without any
particular mental trend. Ataxia increased steadily; she had occasional apoplectic
attacks and convulsions. Death occurred after two years in the hospital.
G. F. (236), age sixty years; duration before admission, one month. He
became gradually childish, forgetful, and irritable. When admitted he was disoriented, and his memory was poor. The knee-jerks were absent, and the pupils
unequal and slow; his speech was slurring and distorted. There were marked
tremors and Romberg's sign. He deteriorated rapidly and died after fourmonths in the hospital.
M. D. (242), age thirty-seven years; duration eight months. The onset
seemed to date from an injury to the head. There was a probable history ofsyphilis. He was depressed, confused, and had attempted suicide. His memory
was poor, and he was much demented. The knee-jerks were exaggerated; andthe pupils unequal and Argyll-Robertson sign present; his speech was ataxic.
There were tremors and occasional convulsions. He died after four months in
the hospital. The total duration of the disease was one year.
F. B. (299) (figure I), age fifty-eight years; duration before admission, onemonth. There was a probable history of syphilis. He was depressed and whining, and had typical paretic ideas, such as that his bowels never moved, and that
he had an incurable disease. He would point to a leg or an arm and say, " See,
it's all dead, all gone,--there's no hope." His orientation and memory showedmarked defects. The knee-jerks were slightly exaggerated, the pupils slow, hisspeech was distorted, and tremors were excessive. The spinal fluid showed pronounced lymphocytosis and a positive Wassermann-Noguchi reaction. Deathoccurred after eleven months in the hospital.
N a t u r a l l y the first q u e s t i o n t h a t arises is, A r e these n o t cases o f
c e r e b r a l s y p h i l i s i n the n a r r o w e r s e n s e ?

I n r e p l y to this we canb u t r e v i e w b r i e f l y t h e d i f f e r e n t i a l points.

T h e y all s h o w e d , i n t h e i rclinical course, a diffuse, p r o g r e s s i v e d e t e r i o r a t i o n i n all the m e n t a lfields, a n d n o t the demence lacu~aire so o f t e n o b s e r v e d in s y p h i l i t i cb r a i n disease.

There

manifestations.

T h e s e p o i n t s are a d m i t t e d l y n o t c o n v i n c i n g , f o r itw e r e i10 c r a n i a l s y m p t o m s o r o t h e r

focal

is possible f o r a n old s y p h i l i t i c e n d a r t e r i t i c - m e n i n g i t i c c o n d i t i o n to

Hideyo Noguchi and J. W. Moore.

237

simulate paresis so closely as to be indistinguishable by its clinicalfeatures from the latter disease. It is upon the post-mortern findings that the diagnosis must depend. Anatomically the brains of
our cases showed the usual pial thickening, more marked over thefrontal convexity. In two it was also prominent over the gyri recti,
cerebellum, and cisterna, but it did not assume the degree of meningitis usually seen in syphilis of the base. In one case (235) there
was an old hemorrhagic membrane beneath the dura; in another(131) there was a marked preponderance of the paretic process in
the right hemisphere, but these conditions were not represented
clinically and the findings were otherwise typical. In the microscopic examination the meningeal process in all cases was diffuse,being more marked in the frontal region. The vessel infiltration
was also diffuse and found at all depths of the cortex and in themarrow. Plasma cells were, in each case, numerous and usuallyoutnumbered the lymphocytes. RQd cells were always present.
The nerve cell alterations and changes in the neuroglia do not present differential characteristics and will not be enumerated. With
regard to the vessels, a number of our cases, as in all generalparalysis material, showed endarteritic changes. In six there wasdefinite thickening of the vessel walls of the type described assyphilitic. In no instance did the intimal proliferation embarrass
the lumen to any extent. In the remaining cases the vessels appeared normal. It seems hardly possible that the presence of thespiroch~etm could be traced to the luetic endarteritis, since they werenot found associated, at least with those vessels which are visible
with the Levaditi stain. In none of the cases were there softenings,
and no gummata were found either in gross or microscopically.
The spiroch~et~e were found in all layers of the cortex with theexception of the outer, or neuroglia layer. One was located at
the border of this layer, 'but not within it. A few were foundsubcortically. Careful search of the pia failed to reveal any of theorganisms. In all instances they seemed to have wandered into thenerve tissue. They were not found in the vessel sheaths and seldom
in close proximity to the larger vessels. There seems to be noratio between the number of spirocha~t~e and the severity of the238

Demonstration of Treponema pallidum in the Brain.

paretic process, although the case in which they were most numerous showed excessive paretic changes.
W h e t h e r or not, by improving the technique, Treponema pallidum
can be demonstrated in a much higher percentage of paretic cases
will be determined by f u r t h e r investigations.
EXPLANATION OF PLATE 5o.
FIG. I. Treponema pallidum in the cortical layer of the right frontal area ofthe brain (case 299). Stained, with slight modification, by Levaditi's method.
X I,100.

T H E JOURNAL OF E X P E R I M E N T A L MEDICINE VOL. XVII.

PLATE 50.

FIG. I.
(Noguchi and Moore: Treponema pallidum in the Brain of General Paralysis.)