FETAL TOXOPLASMIC ENCEPHALITIS--A TYPE OF

CONGENITAL CEREBRAL DISEASE

PAUL M 9 LEVIN, M.D., AND HALCUIT ~V[OORE,M . D .

DALLAS, TEXA~

ITHIN the past few years, d u e c h i e f l y to t h e clinicopathologic

W s t u d i e s o f W o l f a n d his associates, 1 a n e w c l i n i c a l e n t i t y h a s b e e n
d e s c r i b e d . I t is a n i n f l a m m a t o r y d i s e a s e of t h e c e n t r a l n e r v o u s s y s t e m
c a u s e d b y a p r o t o z o o n , Toxop,lasma hominis. A l t h o u g h h u m a n i n f e c t i o n
w i t h t h i s o r g a n i s m o c c u r s a t all a g e s of life, its m o s t s e r i o u s c o n s e q u e n c e s
r e s u l t f r o m i n f e c t i o n of t h e y o u n g i n f a n t o r f e t u s . A t t h i s a g e it is o f t e n ~
fatal, the most prominent pathologic findings being disseminated necro-
t i z i n g l e s i o n s o f t h e b r a i n a n d e h o r o i d l a y e r o f t h e eyes. T h e c e r e b r a l
l e s i o n s u s u a l l y b e c o m e c a l c i f i e d , a n d t h e eye g r o u n d s s h o w m a s s i v e a r e a s
of chorioretinitis. In surviving patients the clinical manifestations
c o n s i s t of r e t a r d a t i o n of m e n t a l a n d n e u r a l d e v e l o p m e n t a n d t h e con-
vulsive state.
T h e f o l l o w i n g is a d e s c r i p t i o n of a ease we h a v e o b s e r v e d , p r e s e n t i n g
t h e c h a r a c t e r i s t i c c l i n i c a l p i c t u r e of f e t a l t o x o p l a s m o s i s : intracranial
caieification, mental retardatr0n, convulsions, and ehorioretinitis.
G. F. H. was born on Aug. 11, ]940, after an easy spontaneous .delivery. There
was no asphyxia or jaundice 9 The mother ha.(] previously had Tric,homona~ v ag~na.lis
v~ginitis, but this had subsided before this, her first pregnancy. The prenatal care
had been thorough, the only maternal illness being a mild attack of coryza in the
eighth month of pregnancy 9 :Fetal activity began at four and one-half months and was
vigorous throughout the remainder of the pregnancy. The circumference of the head
at birth was twelve and three:fourths inches. At the age of i month the infant
developed a skin lesion which was considered to be atopic dermatitis of mild degree
and which promptly improved under ointments and ultraviolet irradiation. At 2
months of age his gums became swollen but the teeth did not erupt until the age
o2 9 months9 Otherwise he seemed to be normal and grew rapidly until he had
his first convulsion at the age of 31~ months.
At this time, on Nov. 24, ]940, he had a sud~den attack of retraction of the
head and cyanosis for a few seconds. This was followed several hours later by a
series of four generalized convulsions, with extensor rigidity of all extremities~
opisthotonus, staring of the eyes, and apnea with eya~losis. Each lasted about one
minute and was followed by stupor and crying for an hour. He became irritable;
jarring of the bed seemed to make him jump, stiffen his extremities, and clench
his fists.
The general physical examination yielde.d normal findings9 Roentgenograms of
the skull showed several areas of increased density within the cranial shadow.
Other laboratory tests, including urinalysis, determination of the calcium and protein
content of the blood, and intraeutaneous tuberculin tests, gave negative results. The
Wassermann reactions of the blood of both the patient a~d his mother were likewise
negative 9
From the Departments of Xeuropsychiatry and Pediatrics, Baylor University Col-
lege of l~Iedicine9
673
674 THE JOURNAL OF PEDIATRICS

The a t t a c k s were somewhat irregular. There were f r e q u e n t minor seizures, re-

sembling a startle p a t t e r n with m o m e n t a r y elevation of the arms. I n t h e severe at-
tacks, which b e g a n with a cry and loss of consciousness, he showed apnea, cyanosis,
t w i t c h i n g o f the face, and either flaccidity or r i g i d i t y o f t h e extremities lasting
one minute. These seizures usually occurred shortly a f t e r awakening, at intervals
o f three or four days. Minor spells were more f r e q u e n t for a .day or so before
each convulsion.

l~ig. 1.--Roentgenogram of the skull, right lateral projection, showing the multiple
areas of intracranial calcification.

On Dec. 25, ]940, he was anesthetized f o r more adequate examination. The

ocular f u n d i wore examined b u t were thought to be normal except for an elliptical
shape of the discs. Spinal puncture yielded fluid under a normal pressure a n d con-
t a i n i n g a slight excess o f protein but a normal amount of cells. Additional stereo-
scopic roentgenogz'ams o f the skull were made (F~g. 1). These clearly showed the
i n t r a c r a n i a l positions o f the calcified areas. There were three clusters of opaque
particles in the ]eft precentral region, one cluster in the right anterior temporal
region, a horizontal linear shadow at the base o f the l e f t temporal lobe, and a vortical
linear shadow in the midline, f a n n i n g out above as if it represented p a r t of the falx
cerebri.
Three days later he had another convulsion and was placed on phenobarbital,
gr. (0.015 Gm.) five times daily. The spells became milder but no less fre-
quent. Doubling the dosage o f the p h e n o b a r b i t a l only made him more drowsy. As
the results of this t r e a t m e n t were scarcely satisfactory, he was placed o11 dilantin
(given i n daily doses as high as 0.16 Gin.). H e then became more alert, b u t the
 LEVIN AND D/IOORE: FETAL TOXOPLASMIC ENCEPHALITIS 675

spells were more severe. A combination of both drugs seemed to give a little better
result than either given separately.
The family history yielded no cases of convulsive .disorder or mental disease in
three generations. The paternal grandmother had had migraine. Roentgenographic
studies of the skulls of the mother and father gave normal findings.
Neurologic examination on Jan. 24, 1941, showed a fairly alert infant, aged
51~ months. He held his head up at times but qpuld not sit alone. The head was
slightly small in relation to the body size, as it had been all his life. A generalized
spasticity of mo`derate degree was present, predominantly of the flexors of the arms,
and adductors of the thighs. The tendon reflexes were lively, and there was fairly
well sustained ankle clonus. The plantar responses were extensor. The pupils were
equal and reacted well to light. The fundi sho~wed pallor of the nasal portions of
both optic discs and several large areas of old chorioretinitis (Fig. 2). These were
located in the lower temporal portion of the right fundus and in the upper temporal
and lower nasal portions of the left. They were all sharply outlined and showed,
yellowish white patches with accumulations of pigment, chiefly at their margins, b u t
also within the atrophic areas. The vitreous was clear, and there were no hemor:
rhages or areas of edema in t h e retina.

/z'ig. 2.--Photograph of the left fundus. Scattered areas of ehoroidal atrophy and
pigmentary accumulations.

An electroencephalogram was made at this time, with leads placed over the central
region of both sides. The dominant rhythm consisted of waves occurring at a rate
of 3.5 cycles per second, usually synchronous on the two sides. Two clinical minor
attacks took place during the recording, each lasting about one second. During the
attacks there was a synchronous onset of irreg~alar waves of high voltage, some of
which were sharp; the fully developed wave-and-spike complex characteristic of petit
raUl in Older patients was not seen (Fig. 3). Random waves, singly or in pairs, of
~high voltage also occurred at periods when there w a s no clinical indication of a
seizure.
676 THE JOURNAL OF PEDIATRICS

I n April, 194], t h e convulsions became m o r e f r e q u e n t , occurring daily, t i e was

placed upon sodium bromide, 15 gr. (1 Gin.) d a i l y in divided doses, a n d t h e pheno-
b a r b i t a l a n d d i l a n t i n were discontinued. A f t e r two ,days t h e a t t a c k s decreased
g r e a t l y in frequency. D u r i n g t h e following twelve m o n t h s he h a d only t h r e e m a j o r
attacks, the firss a f t e r a n i n t e r v a l of six m o n t h s . M i n o r seizures have also been
less frequent. H i s n e u r o m o t o r development has, however, b e e n seriously retarded.
A t 20 m o n t h s of age he w a s u n a b l e to hold h i s h e a d erect for m o r e t h a n 15 seconds
without support, n o r was he able to express h i m s e l f b y words, a l t h o u g h his m o t h e r
described expressive responses b y gesture. Some visual perception seemed to be
present. Microcephaly w a s now a definite f i n d i n g ( F i g . 4).

Z. Do~zal. oo vI

I ) Sea i
Fig. 3.--Electroencephalogram. H i g h - v o l t a g e w a v e s in both central regions occurring
d u r i n g a m i n o r convulsive attack.

Fig. 4 . - - P h o t o g r a p h of the p a t i e n t a t the age of 16 months. Microcephaly.

The ~diagnosis of this case offered considerable difficulty. T e t c h y was first sus-
pected b u t was p r o m p t l y excluded on the b a s i s of n o r m a l chemical findings. The
intracranial calcified lesions raised t h e p o s s i b i l i t y of multiple v a s c u l a r anomalies
of the brain, such as those f o m l d in some cases o f convulsive disorder.2 W h e n the
areas o f chorioretinitis were discovered, it was felt t h a t b o t h the b r a i n a n d choroidal
lesions were a p a r t o f a d i s s e m i n a t e d focal disease~ p r e s u m a b l y infectious. W e
 LEVIN A N D MOORE: FETAL TOXOPLASMIC ENCEPHALITIS 677
were at a loss as to t h e etiology of this condition u n t i l we c a m e across the report
of t h e i.dentical s y n d r o m e in i n f a n t i l e ( f e t a l ) toxoplasmosisia L a b o r a t o r y t e s t s for
this disease were p e r f o r m e d by Dr. A l b e r t B. S a b i n at t h e C h i I d r e n ' s H o s p i t a l , Cin-
cinnati, to w h i c h city the p a t i e n t a n d his f a m i l y m o v e d in A u g u s t , 1941. Dr. S a b i n
h a s s u m m a r i z e d t h e r e s u l t s of these t e s t s in Table I.

TABLE I
'4
TOI~OPLASI~A COIV[PLEMENT FIXATION WITH ]~. SERA

T O X O P L A S M A ANTIGEN + CONTt~OL ANTIGEN +

NAME SPECIMEN
UNDIL. 1 : 2 1 : 4 1 : 8 1:16 UNDIL. 1 : 2 1 : 4 1 : 8 1:16
~, H . Oct. 21, first t e s t ++++ ++-~ ++++ + 0 0 0 0 0
(pa- Oct. 21, s e c o n d t e s t +q-k+ 0 0 0 0 0 0 0
tie=t) Dee. 5 I l l l -[-H--~+ ~ + +++§ + 0 0 0 0
~ r s . I-I. Oct. 21, first test ~-++ 1++++ 0 0 0 0
(Moth- Oct. 21, second t e s t IIII 0 0 0 0 0
er) Dee. 5 ++q-k ++ 0 0 o
Dee. 5 0 0 0 0 0 0
(Fa-
ther)
T o x o p l a s m a a n t i g e n : Saline e x t r a c t of frozen a n d t h a w e d infected rabbit brain.
Control a n t i g e n : Saline e x t r a c t of frozen a n d t h a w e d n o r m a l rabbit brain.

A d d i t i o n a l i n f o r m a t i o n was s o u g h t c o n c e r n i n g t h e possible a c q u i s i t i o n of a texo-

plasmi~ infection. I t was l e a r n e d t h a t the f a m i l y cat ( P e r s i a n v a r i e t y ) h a d been
sick several weeks b e f o r e t h e p a t i e n t was born. T h e s y m p t o m s of t h i s illness were
weakness, v o m i t i n g , loss of appetite, a n d a t e m p e r a t u r e o f 108 ~ F . A relapse occurred
s h o r t l y a f t e r t h i s illness. F i n a l l y t h e cat a p p e a r e d to h a v e recovered a n d was given
away. I n v e s t i g a t i 0 n revealed t h a t the eat was f o u n d d e a d i n A u g u s t , 1941, and
was cremated. M a n y wild r a b b i t s lived in the n e i g h b o r h o o d of t h e p a t i e n t ' s home,
a n d several y o u n g ones h a d b e e n killed b y t h i s cat.

COMMENT

An early onset, probably intrauterine, of the disease in this patient is

suggested by the following factors : The cerebral lesions were calcified at
the age of 31/2 months and, judging by their appearance in later roent-
genograms, they were already completely healed. The areas of chorio-
retinitis, when discovered, also gave the appearance of a quiescent stage.
A mild microcephaly was present since birth, and the degree of this
condition did not change as the patient grew older. Finally, serologic
evidence of infection in the mother but not in the father is consistent
with the possibility of prenatal infection.
Before the discussion of toxoplasmosis, comment upon and qualifica-
tion of th e serologic tests should be made. Both complement fixation and
rabbit protection tests were carried out by Dr. Sabin. Specific comple-
ment fixation antibodies were consistently demonstrated in several speci-
mens of blood from the patient and mother. IiIowever, no neutralizing
antibodies were detected by rabbit tests made with the same blood
samples. This discrepancy is unusual. As Dr. Sabin wrote us (Jan. 15,
1942) :
" S u c h a situation has not been encountered before in our work with
toxoplasma. Our experience has rather been the reverse; namely, that
678 THE JOURNAL OF P E D I A T R I C S

the complement fixation tests a p p e a r e d to be either less sensitive or could

be obtained less frequently t h a n the neutralization test. Thus we have
a considerable n u m b e r of sera which h a v e neutralizing antibodies for
toxoplasma but no complement fixing antibodies. T h u s far; the H.
sera are the only ones in which the reverse obtains. Because of this
peculiar behavior of these sera, I am not p r e p a r e d to say, although the
complement fixation tes~ appears to be specific to the best of our knowl-
edge, t h a t the results obtained with the s e r u m of the child and the mother
represent unequivocal evidence of toxoplasmic infection some time in the
past. ' '
:From a clinical standpoint the findings in this case are entirely typical
of toxoplasmosis of p r e n a t a l inception. The effects of this infectious
process seem to differ according to the age at which infection occurs.
Of 17 cases of this disease t h a t have been r e p o r t e d p r i o r to this case,
eleven had an onset of dlinieal manifestations either at birth or shortly
thereafter4; in nine o~ these, death had occurred, a n d the diag~qosis was
established at autopsy, while in the r e m a i n i n g two the patients were still
living at the time of the report. These eleven infantile cases presented
a symptomatology that was strikingly u n i f o r m and, to our knowledge,
specific for toxoplasmosis. Focal areas of necrosis of the b r a i n which
usually became calcified were present in all cases. These resulted in
microcephaly unless, as happened in several instances, there was an
associated stenosis of the aqueduct of Sylvius with obstructive hydro-
cephalus. Convulsions were almost u n i f o r m l y present, as was mental
deficiency. In one instance there was a necrotic lesion of the spinal
cord, with microscopic loci in other cases. I n addition to the encephalitis
or encephalomyelitis, there is usually also a focal necrotizing chorio-
retinitis. These lesions are massive, l a r g e r t h a n those seen in cases of
disseminated chorioretinitis of congenital syphilis. I n one instance there
was an unilateral microphthalmia. General pathologic observations in
the few cases with complete autopsy included widespread dissemination
of the toxoplasma in one case and scattered areas o~ inflammation of
striated muscle, including the myocardium, in two others.
Onset in childhood was seen in two cases o~ this disease, s I n both
there was a brief illness with convulsions, mental confusion, a n d a
mononuclear pleocytosis of the eerebrospinal fluid. Recovery without
evident residual defect (at least not for a period of several months),
took place in one case, and in the other the child died and showed at
autopsy (which was limited to the brain a n d spinal cord) microscopic
loci of necrosis and irregular cellular infiltrations. Three instances of
the disease have been described in adult life, ~ with clinical features
simulating the typhus-spotted fever group. A m a c u l o p a p u l a r erup-
tion of the skin, weakness, and fever were present in all three. I n one
ease the patient beeame m a r k e d l y cyanotic a n d i r r a t i o n a l and died in
coma two days later. A second patient became irrational and d e a f .
 LEVIN AND MOORE: FETAL TOXOPLAS~r ENCEPHALITIS 679

Autopsies of these cases showed minute areas of necrosis in various or-

gans, with rare microscopic inflammatory lesions in the brain. Parasites
were found throughout the body, notably in aggregates within myo-
cardial fibers.
Toxoplasmic infestation is more common in man t h a n would be judged
from the paucity of the reported cases of the clinical disease, since the
mothers of children with infantile toxoplasmosis m a y show immune
bodies in their blood, a How widespread the toxoplasma parasite occurs
in m a n remains to be studied.

SUMMARY

F e t a l toxoplasmosis is a cause of focal encephalitis, with intracerebral

calcification and chorioretinitis. The residual symptoms are convulsions
and retardation of mental and neuromotor development. A case is pre-:
sented with this characteristic clinical picture. Specific complement
fixing antibodies were demonstrated in the blood of the patient and
mother.
We wish to thank the following physicians for observations which they kindly
made after the p~tieut's removal to Cincinnati, Ohio: Dr. Albert ]3. Sabin, immuno-
logic tests; Dr. D. J. Lyle, photograph of retina; Dr. Ci R. l~itershofer, clinical ob-
servations.
REFERENCES
1. Wolf, A., and Cowen, D.: Bull. Neurol. Inst. New York 6: 306, 1937; Wolf, A.,
Cowen, D., and Paige, ]3. H. : Am. 3-. Path. 15: 657, 1939.
2. Geyelin, ~ . 1~., a~d Pen:field, W.: Arch. 2~eurol. & Psychiat. 21: 1020, 1929;
~Iiehael, ft. C., and Levin, P. ~ . : Arch. Neurol. & Psychiat. 36: 514, 1936.
3. Wol~, A., Cowen, D., and Paige, ]3. I:L: Science 93: 548, 1941.
4. 5anku, 5. : Cited by Wolf, Cowen, and Paige;1 Torres, C. M. : Compt. read. Soc.
de biol. 97: 1778, 1927; de Lange, C.: Ztsehr. f. d. ges. Neurol. u. Psyehiat.
120: 433, 1929; ]~ichter, 1~.: Arch. Neurol. & Psychiat. 36: 1085, 1936;
Wolf, A., and Cowen, D.: B u l l Neurol. Inst. New York 7: 266, 1938; Wolf
and Cowen and Wolf, Cowen, and Paige;1 Wolf, Cowen, and Paige;3 Paige,
]3. It., Cowen, D., and Wolf, A.: Am. J. Dis. Child. 63: 474, 1942.
5. S~bin, A. ]3.: J . A . M . A . 116: 801, 1941.
6. Pinkerton, H., and Weinman, D.: Arch. Path. 30: 374, 1940; Pinkerton, It.,
a~d IKenderson, 1~. G. : J . A . M . A . 116: 807, 1941.
]711 :PACIFIC AVENUE
4105 :LIVE OAK STREET