Toxoplasmosis
Dr. Anil B. Jalan
M.D. , D.C.H.
Introduction :- Toxoplasmosis is a very common disease of world wide distribution. It is caused by Toxoplasma gondii, which is an obligate intracellular protozoan, ubiquitous in nature. Toxoplasma was first found in gondi, a North African rodent .
Toxoplasma infection in the human infant was first described by Wolf and associates in 1939.
The incidence of congenital infection in the human has been estimated at 1 per 1000 to 3,500 live births, and when stillbirths are included , about 1 % of all pregnancies .
The natural host of Toxoplasmsa gondii, is the cat ; however , it also occurs by chance in humans, a large group of domestic mammals ( dogs , swine , sheep , cattle , goats ), certain rodents , some birds , and a few other animals.
These infections can be classified into four groups :-
1. Those acquired by immuno-competant individuals .
2. Those acquired by reactivation of the disease in immuno-compromised individuals.
3. Occular Toxoplasmosis, usually chrioretinitis from congenital infection .
4. Congenital Toxoplasmosis due to acute symptomatic or asymptomatic infections of the mother during pregnancy and leading to infection of the infant .
It is transmitted by :-
1. Ingestion of oocysts excreted in the feaces of infected cats that contaminated dust , soil and litter box material.
2. Consumption of tissue cysts in undercooked or uncooked meat and certain organs of infected eggs.
3. Transmission has been known to occur by the transfusion of blood or blood products.
4. Transplacental transmission which often leads to severe and life long disabilities in the infected infant.
5. Organ transplants like Cardiac transplant and Liver transplant.
Infection with the parasite occurs among all age groups, and as a consequence, serologic evidence of it increases with increasing age. A number of investigations have shown that , depending on the age and geographic location of the population studied, as much as 93 % of the population has been infected.
Toxoplasma gondii is an intracellular parasite which has emerged as the second commonest opportunistic infection in AIDS patients, with as high as 75 % mortality . In immunologically competant subjects it may have a mild course of manifestations and usually persists latently for life long.
Asymptomatic patients :- The initial infection with T. gondii is commonly associated with no symptoms or an illness which is so mild that it is looked upon as a harmless and very temporary inconvenience ascribed to a virus, and is usually poorly remembered.
Symptomatic patients :- demonstrate
1. Fatigue and adenopathy in the absence of fever.
2. Occasionally the illness is characterized as infectious mononucleosis like and marked by -
a. headache
b. malaise
c. fatigue
d. fever
e. adenopathy
f. sore throat
g. muscle pain.
h. Rarely , there is maculo-papular rash
i. enlargement of the liver or spleen
j. monocytosis
The initial infection is self limited, becomes chronic ( latent ) , and poses no serious risk unless the host is immuno-compromised, in which case it frequently involves the central nervous system ( CNS ) & lungs and is often fatal .
Seroprevalence of Toxoplasma antibody in Europe and USA varies between 50 - 60 % and ranges between 4 - 9 % in India .In pregnant women on the worldwide scale , there are seroprevalences from 7 % to 51.3 % and in women with abnormal pregnancies and abortions , the sero-prevalence vary from 17.5 % to 52.3 %.
The Pregnant Women : Incidence :- Although toxoplasmosis is a problem throughtout the world , its frequency varies from one geographic area to another. Accordingly, the number of susceptible women of child-bearing age differs from one place to another.
Prospective studies of pregnant women shows susceptibility to be :-
1. Brussels - 47 %
2. Oregon - 92 %
3. West of scotland - 75 %
4. Paris - 25 %
5. Oslo - more than - 99 %
Even within relatively small geographic units there are groups of different vulnerbility.
1.For example, in Alabama prenatal serologic screening has indicated that two thirds of the pregnant women in rural areas are susceptible, while that is true for 80 % of urban poor and 75 % of middle and upper - class urban gravidas .
2.The higher frequency of susceptibles does not indicate a greater chance of infection since it reflects a lower incidence of the disease .
From the studies it is estimated that 1 in 200 to 1 in 1000 women contracted toxoplasmosis during the pregnancy .
1. Oregon 1 in 200
2. Paris 1 in 250
3. Scotland 1 in 250 to 1,500 ( in various parts of Scotland )
4. New York City 1 in 500.
5. In general ,acute toxoplasmosis occurs in about 2 to 7 of every 1,000 pregnancies and that the frequencies remains within that range because there are few susceptibles in areas of high frequency and the frequency is low in areas with many susceptibles .
Table no. 1 :- Indian Studies for prevelance of Toxoplasmosis in women of childbearing age :-
Mahajan R.C. et.al. ( 5.2 %) Chandighar
Chakraborty P. et.al. ( 7.7 % ) Calcutta
Bhatia V.N. et.al. ( 8.4 % ) South India
Thokar M.A. et.al.( 26.9 % ) Kashmir
1 .Prevalence of Toxoplasmosis in Indian Pregnant women is 7.7 % ( Chakraborty P. et.al )
2 . Places where seroprevalence of Toxoplasmosis is high , serological screening test is advisible for all pregnant women as early as possible , at least by 10 - 12 weeks of prenancy and should be repeated at 20 - 22 wks of gestation, when the initial test comes seronegative .
3 . Seronegative women should be advised to avoid infection by preventing exposure to cat feaces, undercooked or uncooked food, especially the meat .
4 . ELISA screening test is better than Latex test and should be performed where facilities for the same exist .
Guidelines - 1 :- As part of the routine antenatal screen in first trimester, if the toxoplasma Ig G antibody is positive, the patient is immune, at no risk and reassurance is all that is needed. No repeat testing is required. If the Ig G and Ig M are negative, the patient must be followed up later in pregnancy at monthly intervals , atleast once in second trimester and then in third trimester to detect seroconversions and treated accordingly to minimize the damage to the fetus.
Transmission may occur in imunocompetant women when they acquire infection within 6 - 8 wks. before conception.
Most dangerous period is 2nd to 6th month of pregnancy .
Infections during the third trimester are more common and usually result in subclinical disease. These are initially relatively benign with the infection being latent for at least the first few years of life .
Symptoms :- From the stand point of symptoms , toxoplasmosis is the same among pregnant women as among nongravidas; only 10 % with the acute disease are symptomatic. The organisms invade the placenta if the infection occurs during pregnancy but, rarely if ever, if the disease antedates the pregnancy. The later in pregnancy the acute infection, the more likely is the placenta to be involved at the time of delivery. From among untreated women with toxoplasmosis, Desmonts and Courveur were able to isolate Toxoplasma gondii at term from 25 % of the placentas of women whose infection begun during the first trimester, 54 % if the onset was during the second trimester, and 65 % if the disease was contracted during the third trimester .
Effects on Pregnancy :- Of every 1000 pregnant women , upto 8 become infected , and the infection is transmitted to the fetus in approximately 40 % of the cases. If the pregnant woman is infected before conception, there is no risk of transmission of the organism to the fetus. Maternal antibodies acquired from the infection prior to pregnancy prevent fetal infection.
Ig G antibodies can be transferred passively from the mother to the fetus across the placenta. Ig G antibody titre is present in a newborn by the third month of life . For detection of Ig M antibody , the ELISA method is preferred because of its greater sesitivity . The demonstration of Ig M antidbodies in th neonate is diagnostic of congenital Toxoplasmosis .
The effect of the illness acquired during pregnancy on the occurance of spontaneous abortions and stillbirths is not certain.
1. Desmonts and Couvreur found evidence suggestive of an increase in pregnancy losses, but the data are not clear.
2. Koppe et.al. found no pregnancy losses among 1,821 women who acquired toxoplasmosis just before or during pregnancy,
3. Feldman and Miller also failed to find an association .
4. Stray - Pederden prospectively studied 54 women at some risk of problems from toxoplasmosis and noted two abortions and no stillbirths among 13 pregnancies in which the infection began during gestation; no abortions or stillbirths occurred among the 41 women whose disease appeared shorlty before they became pregnant or who had long standing disease. Yet he and others studied the aborted products, endometrial tissue, and uterine blood from 41 habitual aborters and found tachyzoites of T. gondii in the material from 6 while no organisms were found in material from 20 sporadic abortions .
5.Finally , in their study of 746 pregnancies at risk for congenital toxoplasmosis , Daffos et. al. reported no spontaneous abortions ( 24 pregnancies were terminated on request of the mother ) and no stillbirths. One poorly documented report of only ten cases incriminates gestational toxoplasmosis as a cause of premature labor , but none of the many large prospective studies of the infection during pregnancy indicated such an association. Pregnancy does not cause reactivation of latent disease .
1. Desmonts et.al. : ? increased fetal losses.
2. Koppe et.al. : No fetal losses.
3. Feldman & Miller : No fetal losses.
4. Stray & Pededen : ? increased fetal losses.
5. Daffos et.al. : No fetal losses.
Serodiagnosis :- The diagnosis of toxoplasmosis is based on antibodies present in the serum.
1. The sabin-Feldman dye test The dye test is probably the most sensitive test. Titres appear within 2 wks. of the infection, persist until age 2 yrs. at levels of 1 to 1000, and gradually decline to around 1 to 50 or less by age 5 years .
2. Indirect immunofluorescent antibodies ( IFA ) test :- can be used to provide quantitative measurements of specific IgA antibodies against T. gondii. Some have found difficulty in being confidant of the quantitativeness of the IFA test. They reach their peak 1 to 2 months after the onset of infection and, unfortunately, remain at high levels for years. The peak dye test values ranges form 1,000 to 4,000 IU / mL . Among pregnant women who are seronegative, these are excellent tests to use serially to detect newly acquired infections, Seroconversion of patients previously without demonstrable antibodies or increasing titers ( four fold rise ) in seropositive patietns are indicative of recently contracted active infection .
3. ELISA :- Because high levels of these antibodies persist , it is important to know the titres of specific IgM antibodies as measured by the double - sandwich Enzyme Linked Immuno Sorbant Aggulatintion assay, which becomes evident about 2 weeks after the onset of the infection, peak at a month, and decline to extinction over the following 5 to 6 months; exceptionally, positive tests may be present for up to 2 years .
4. P.C.R. techniqe :- Most specific method, but is quite costly and not easily available for routine diagnostic purposes.
Microscopy :- Although serologic means are most often used to diagnose toxo-plasmosis, the parasites may be demonstrated microscopically in body tissues or fluids has been inoculated intra-peritoneally into albino mice or placed in tissue culture media. It is not an esay matter to find the tachyzoites with ordinary stains, but excellent results are obtained, even in fixed specimens, with the fluorescent antibody and the peroxidase - antiperoxidase techniques .
Tissues most commonly used for study are
1. Lymph nodes .
2. Placenta .
3. Blood obtained from the uterus or vagina immediately following delivery .
4. Amniotic fluid.
5. Clot of umbilical cord blood obtained during amniocentesis .
The CNS can be severely affected in patients with congenital infection, those treated with immunosuppressant drugs and patients with AIDS .
In these cases , acute focal or diffuse meningoencephalitis with extensive areas of brain necrosis and vascular involvement may be observed . Toxoplasma proliferates in the ependymal and subependymal regions and spreads widely. Morphologic changes include lymphocytic infiltration of the meninges, destructive lesions of both brain and white matter, and focal periventricular and periaqueductal calcification.
In immunodeficient adult patients, the major finding is necrotizing encephalitis ; large abscesses can occur.
Ocular lesions include :-
1. Acute chorioretinitis with severe inflammations and necrosis.
2. Necrotizing retinitis
3. Granulomatous chorioretinitis .
The mycocardium and skeletal muscles may contain tissue cysts without inflammation, or there may be widespread myositis .
Intrauterine Investigastion :- In 1985 , Desmonts et al. described a technique for the diagnosis of toxoplasmosis in the fetus that includes an amniocentesis to obtain amniotic fluid and, at the same time, an umbilical vein needle puncture done under sonographic guidence ( cordocentesis ) to obtian fetal blood. The amniotic fluid is centrifuged and the sediment is inoculated intraperitoneally into mice or placed in tissue culture media. The fetal blood is determined to be free of maternal blood by the Kleihauer - Batke stain or by hemoglobin electrophoresis. It is centrifuged , and the sediment is inoculated into mice or placed in tissue culture media ; the serum is used for serologic studies . In 1988 , the same group reported the benefits of this methoud of evaluation and the advantages of its use as a basis for therapy and continuation of pregnancy .
Treatment :-
1 . Control studies in humans have shown that treatment during the postnatal period may prevent development of serious sequele in both symptomatic and asymptomatic infected infants.
2 . Life long secondary prophylaxis is indicated for all patients previously treated for toxoplasma encephalitis .
3 . Seronegative patients who receive organs from seropositive donors are at risk for serious disease , and prophylactic treatment may be indicated.
Drugs used are :-
1. Pyrimethamine .
2. Sulfadiazine.
3. Trimethoprim.
4. Spiramycin.
The treatment of toxoplasmosis has not been a triumph of modern medicine . In the United States there appeatrs to be no sense of urgency since the disease is usually undiagnosed , self limited, and not considered to be a major health problems. The efforts of European workers have been more fruitful but not highly successful .
The standard treatment in the united States, for those who required it, is limited to a combination of the antimalarial pyrimethamine and a sulfomnamide, most commonly sulfadiazine in equal parts. The combination provides a decided synergistic effect. Both components of the regimen are capale of causing problems of toxicity, and their benefits are not exciting. Careful and frequent examination of the patient?rine are required to assess the need for modification of the dose or sulfinamide used based on the appearance of crystalluria or hematuria. Because pyrimethamine is a folic acid antogonist, folinic acid ( leucovorin calcium ) is always used with it .
Trimethoprim , another antimalarial agent , has not been found to be reliably effective. Sulfisoxazole is not effective and is not to be used. Studies of small rodents indicate a teratogenic effect of pyrimethamine that is significantly reduced following the addition of folinic acid .Both pyrimethamine and trimethopeim have been clasified as category C with regard to their level of risk for the fetus other than a questionable association with Niikawa - Kuroki syndrome in one infant .
In most countries , the favored agent for the treatment of acute toxoplasmosis during pregnancy is spiramycin, which is not approved for use in the United States. Nevertheless, it may be obtained upon application to the Centres for Disease Control in Atlanta . A single effective regimen for spiramycin treatment has not been presented, although various plans have appeared. However spiramycin is freely available in India.
Spiramycin is relatively a safe drug that concentrates in the placenta and may reduce the risk of maternal - fetal transmission by 60 % without having any effect on the fetus .
If the fetus is shown to be infected, the combination of pyrimethamine, sulfonamide(s), and folinic acid is added for the duration of the pregnancy. There are oppenents of the invasive intrauterine diagnostic procedures and subsequent treatment of elected pregnant women because they are not impressed that the regimen advocated is truly helpful .
Patients have also used a combination of pyramethamine , sulfadiazine , pyrimethamine , and clindamycin for the treatment of toxoplasmosis encephalitis , and the results are comparable .
Guidelines - 2 :-
1. Seropositive ( Ig M antibody Positive ) pregnant women - Sulfadiazine 1 gm. 6 hrly and pyrimethamine in a single dose of 75 mgm followed by 25 mgm daily , both for four weeks, with folic acid 10 mgm daily.
2. Moniter blood count at weekly intervals and antitoxoplasma antibody titres at 2 monthly intervals.
3. Alternatively Spiramycin Cap. 500 mgm Q.D.S. for 21 days and then 2 wks. gap with repeat cycles till the end of pregnancy may be used.
4. At birth cord-blood IgM of Toxoplasma should be done.
Elective Termination of Pregnancy :- Because of the occurrence of serious untoward effects among infected fetuses and the less than clearly effective therapy , many women who have become infected during pregnancy have chosen to resolve the potential problem of having a child with major disabilities by undergoing an abortion . In addition ,many cannot tolerate the continuing anxiety brought on by the possibility of severely limiting unresolvable problems . For these reasons as well as others, it is important to properly assess susceptible pregnant women for Toxoplasma infection serially early in pregnancy .
Followup of infection detected during pregnancy :-
1. Serological followup .
2. USG followup for head size.
3. USG followup for Ventricular size.
1 . Desmonts and Couvreur have suggested that serologic evaluation be done monthly or bimonthly.
2 . Additionally , if infection occurs during pregnancy , it may be of benefit to perform serial sonographic studies of the fetal head to determine whether there is abnormal ventricular size .
In countries where interruption of pregnancy is permitted beyond the 20th week , that information may be helpful to mothers undecided about abortion . Also , it will be of benefit to those responsible for the care of the infant in the assessment of the ventricular size following birth and in making plans for management .
THE FETUS AND NEWBORN
Frequency of Intrauterine Infection
Chronic , latent , or long - standing toxoplasmosis is no threat to the pregnant woman , her fetus , or her newborn infant . The acute disease contracted during pregnancy is a very small danger to the gravida but a serious one to her offspring because Toxoplasma organisms sometimes gain access to the placenta and the fetus . The studies of Desmonts and Courveur show that if treatment of the mother is disregarded and the onset of the infection is during the first trimester , the chance of infection in the newborn is 10 % to 15 % ( some studies say upto 25 % ) and the consequences will be severe in two thirds ; if the onset is during the second trimester , about 30 % will be infected at birth , nearly 10 % of which will be severe ; if the disease is contracted during the last trimester , approximately 60 % of the neonates will be infected , and virtually none will be severe .
The investigations of Teutsch et al . are in close agreement but tend to indicate a slightly greater chance of severe disease among the infants whose mothers become infected during the first two trimesters .
Because the relationship of congeni-tal infection is only with toxo-plasmosis acquired during gestation , a woman will not give birth to more than one congenitally infected infant except when the disease appears during a pregnancy that has produced multiple offspring .
There are many instances of infected monozygotic and dizygotic twins and occasions in which only one of twins has been afected . Infected twins , irrespective of their zygosity , may be equally or singly involved . When both are infected they are not always of comparable severity . Only once has congenital infection in successive pregnancies been suggested , and that account is of questionable validity .
Toxoplasma reactivation is known to occur in immunocompromised indivi-duals and several cases of congenital Toxoplasmosis following reactivation of chronic infections in HIV - infected mothers have been described , even in consecutive pregnancies .
Guidelines - 3 :- The routine screening of all pregnant women has been instituted in France and Austria and provides an opportunity for early identification of primary infection and treatment - followup of the newborn. In study by Guerina et.al. , the test results of 635,000 infants in Massachussetts and New Hampshire for indications of congenital toxoplasmosis , found 52 confirmed positive cases by testing blood specimens collected on filter paper at birth. Serologic Ig G & Ig M ELISA were used for confirmations , almost all ( 50 ) of the confirmed cases wouldnot have been identified had they not been screened for Toxoplasmosis. ( incidence 1 : 12,212 )
Effects on fetus :-
1. I.U.G.R.
2. Organ involvemnet
3. Microphthalmia
4. Congenital cataracts
5. Heart valvular defects
6. I.U.F.D. / Still births ( ? )
Intrauterine Growth Retardation :- Intrauterine growth retardation of infants infected during gestation has been reported in one , ten - patient poorly documented study, that is at variance with all others. Others identified as being small for dates were term liveborn infants and abortuses that were uninfected . There is no support among the many prospective studies of toxoplasmosis in pregnancy that intrauterine growth retardation is a consequence .
Infection in the Newborn Infant :- At birth , 60 % to 75 % of infants with congenital toxoplasmosis have subclinical infection , that is , there is microbiologic or serologic evidence of the disease in the absence of clinical findings .
Subclinical disease has been documented in newborns of untreated mothers :-
1. Koppe et.al. : 60 % cases .
2. Desmonts & Courveur et.al, : 68 - 75 % cases .
It appears that treatment of the newly infected gravida may result in an improved outcome of pregnancy , but there remains a very high incidence of fetal infection . From Table 1 it can be seen that Desmonts and Courveur , in their study of 542 women who acquired toxoplasmosis during pregnancy , demonstrated that spiramycin was protective of the fetus . Oddly , they encountered about the same frequency of inapparent disease at birth among the infected infants of treated and untreated mothers .
Data from Desmonts , Courveur : Congenital Toxoplasmosis : A prospective study of the offspring of 542 women who acquired Toxoplasmosis during pregnancy .
Treatment Schedule :- 3 wk. courses of 2 - 3 Gm Spiramycin daily taken orally in 4 equally divided doses and repeated after intervals of 2 wks. to the end of gestation.
The indication from carefully done research , that up to 75 % of infants with congenital Toxoplasma infection appear to be nomal at birth, is misleading. Newer serologic tests using IgM immunosorbent agglutina-tion assays are said to be superior to ELISA IgM tests for identifying congenitally infected neonates with low antibody titers .
Realistically, there must be many newborn infants who are erroneously considered to be normal because the most frequent abnormalitites are missed. This is a result of the common failure to perform serial serologic studies during gestation. That denies to those responsible for the care of newborn infants the clues necessary to indicate the need for proper retinal examinations that might reveal chorioretinitis or retinal scarring , radiographs of the skull by which intracranial calcification might be demonstrated , and sonographic studies of the head from which ventricular size can be estimated.
Among the minority of infected infants who present signs and symptoms , the so called triad of toxoplasmosis ( hydrocephalus , chorio - retinitis and intracranial calcifications ) may be present at birth but are usually not evident untill a few months of age .
Potter refers to the Tetrad of Toxoplasmosis :-
1. Hydrocephalus or microcephalus,
2. Chorioretinitis ( particularly of the macular region ) ,
3. Convulsions or other indications of CNS involovement,
4. Radiographic evidence of intracerebral calcification .
Without doubt , the brain is the site of most evident abnormality and , together with the retina , the area most commonly and disasteroulsly diseased .
The excessive signs and symptoms usually and erroneously attributed to congenital Toxoplasma infection of the neonate have been perpetuated by the repetition of findings from a study that incorporated un - sub -stantiated data from a variety of sources in 1947 when knowledge of the newborn infant was meager . Infact , clinical congenital toxo -plasmosis in the neonatal period is either mild to moderate or severe .
Mild to moderate disease :- is usually characterized by one or more of the triad of
1. hydrocephalus ,
2. chorioretinitis ,
3. intracranial calcifications .
C.S.F. findings :- Some patients may be found to have elevated concentrations of protein ( 150 to 1,500 mg / dL ) and lymphocytosis ( 10 to 110 cells / mm ) of the cerebrospinal fluid that can be expected to persist for many weeks or as long as 5 months .
Parasites may be seen in smears of the sediment of centrifuged cerebro-spinal fluid ( CSF ) , and inoculation of the material into mice may produce disease .
Organ involvement :-
1. Rarely , newborn infants with mild to moderate disease will be found to have enlargement of the liver and spleen that may persist for a few weeks .
2. Chorioretinitis may be represen-ted by scars or active disease . Neither indicate whether or not the disease will progress . The clinical course in this group of infants is unpredictable .
3. Those with cerebral calcifications alone tend to do well during the first year or so of life .
4. If hydrocephalus is present , the course will probably be one of progressive ventricular enlargement that will require surgical intervention. Occasionally the hydrocephalus arrests spontan-eously . The preceding relates to fullterm or late preterm infants ; early preterm infants may have a less favorable course and proceed to the severe form several weeks after birth .
Severe variety :-
1. Neonatal Sepsis like picture .
2. Typical severe cong. Toxo. Infection
3. Fetal hydrops
4. Cong. Nephrotic syndrome.
The severe form of the disease in the early days of life may be inapparent only to manifest itself in a few days or weeks . It may have the general characteristics of neonatal sepsis , and if that is the case , death results in a short time .
It may present with  typical picture
1 hydrocephalus ,
2 microcephalus ,
3 hepatosplenomegaly ,
4 active chorioretinitis , or
5 meningo-encephalo-myelitis with
seizure .
There have been infants with congenital toxoplasmosis who were hydropic at birth and initially believed to be suffering from erythroblastosis fetalis .
Others appear to have the nephrotic syndrome as a consequence of renal involvement in the form of glomerulo - nephritis or glomerilosclerosis . The clinical and laboratory features are in keeping with those of the usual nephrotic syndrome of infants and children .
Organ Involvement :- Once Toxoplasma gondii organisms have gained entry to the fetus , they spread wherever the circulation takes them . However , it seems that all tissues do not provide a satisfactory environment since the parasites are not found every where .
Table No. 2 : Organs Involved in 13 infants 31 Days Old or Younger and 1 Stillborn With Congenital Toxoplasmosis .
Involvement in ( % )
1. CNS - 14 / 14 ( 100 % )
2. Hydrocephalus - 6 / 13 ( 40 % )
3. Intracranial Calcification - 9 / 13 ( 59 % )
4. Eyes - 6 / 6 ( 100 % )
5. Heart - 10 / 13 ( 79 % )
6. Lungs - 4 / 11 ( 36 % )
7. Spleen - 4 / 11 ( 36 % )
8. Liver - 1 / 12 ( 8 % )
9.Pancreas 1 / 9 ( 11 % )
10.Gl tract 2 / 5 ( 40 % )
11.Adrenals 6 / 10 ( 60 % )
12.Kidneys 4 / 11 ( 36 % )
13.Bladder 1 / 2 ( 50 % )
14.Testes 2 / 4 ( 50 % )
15.Ovaries 1 / 2 ( 50 % )
16.Uterus 0 / 1
17.Thyroid 1 / 5 ( 20 % )
18.Thymus 1 / 4 ( 25 % )
19.Pituitary 0 / 2
20.Muscle 5 / 7 ( 71 % )
21.Bone marrow 1 / 5 ( 20 % )
22.Lymph node 1 / 4 ( 25 % )
Central Nervous System :- Every infant 31 days of age or younger in the report of Rodney et al. had involvement of the CNS , but only about half had hydrocephalus , and a third more had intracranial calcifications . Every infant with calcifications had ventricular enlargement . The CNS is severely and widely affected . The infection involves not only the meninges but also the cerebellar parenchyma , periventricular areas , brain stem , and spinal cord . Tissue destruction is severe and widespread as a result not only of invasion by the organisms but also from necrosis due to vascular involvement. Calcium deposits occur in areas of necrosis and within damaged cells.
Commonly, there are small granulomatous lesions and pseudocysts .
Characteristic of toxoplasmosis is peri-aqueductal and peri-ventricular necrosis that results from severe vasculitis . It is from these latter lesions that the debris and large quantities of protein appear in the CSF that , in most cases , are responsible for obstruction to the flow of the fluid that leads to hydrocephalus .
In some , parenchymal destruction around the ventricles appears to cause ventricular enlargement as a consequence of brain atrophy .
Hydranencephaly has been described infrequently in association with intrauterine T . gondii infections .
Eyes :- Commonly the retina , choroid , or both are affected at birth , either in the active inflammatory stage or as scarring .
Although Stray - Pedersen found no evidence of eye disease among 13 newborn infants at high risk of congenital toxoplasmosis , others have encountered chorioretinitis or scarring during the first days of life in about 20 % of infected infants .
The lesions may be unilateral or bilateral and , as a rule , are without clinical manifestations in the newborn period . Accordingly , and because ophthalmo-scopy is difficult and best done with an indirect ophthalmoscope , any infant in whom there is the posibility of congenital toxoplasmosis should be examined by a pediatric ophthalmologist .
Lungs :- The lungs are infrequently involved in congenital toxoplamosis unless the disease is very severe and results in death . On those rare occasions , the pathology appears in the alveolar septa as well as the alveolar cells . The organisms may be seen in the lung tissue and endothlium of the vessels and free in the alveoli .
Heart :- Although there are no known clinical manifestations of cardiac malfunction among infants with congenital toxoplasmosis , cysts have been noted in the myocardium on postmortem examination . Sometimes therre is no evidence of tissue response to the organisms , and occasionally , there is round cell infiltration , but severe myocarditis has not been described .
One patient , known to have congenital Toxoplasma infection and followed for many years, developed episodes of paroxysmal tachycardia of unknown cause .
Liver and Spleen :- The liver and spleen are occasionally enlarged in association with congenital toxoplasmosis , but organisms are not evident in them , nor is there demonstrable necrosis or inflammation .
Enlargement , engorge - ment , and enhanced erythropoesis are the only pathologic findings .
Splenic or hepatic dysfunction is not a problem .
Jaundice has been described , but there is no evidence that it is anything more than the usual physiologic jaundice of the newborn .
Kidneys :- The kidneys have frequently been found to demonstrate pathologic and clinical evidence of involvement in congenital toxoplasmosis . A picture of the nephrotic syndrome has been described in which the patients were edematous , serum protein concentrations were low , oliguria was evident , and urinalyses revealed marked proteinuria , casts , and at times , red blood cells . The microscopic changes have been those of glomerulonephritis and glomerulosclerosis as well as acute tissue necrosis and inflammation with occasional organisms being seen . Renal tissue obtained by percutaneous biopsy in the case of Shahin et al. was found to have IgM , fibrinogen , and Toxoplasma antigen and antibody deposited on the glomeruli , thereby indicating a pathogenesis similar to the glomerular disease caused by streptococcal infections . Changes persisted despite treatment for 7 months with prednisone , sulfonamides , and pyrimethamine .
It is evident from that many organs have been found to be involved in congenital toxoplasmosis , but aside from those mentioned above , none have been proved to cause clinical manifestations .
Effects of Treatment During Pregnancy and Sequelae of the Disease :-From the reports of Desmonts and Courveur , the benefits to the fetus and newborn of spiramycin treatment provided the mother during pregnancy appear to be significant . Based on isolates of the organism from the placenta at birth , the advantages seem to be most marked if spiramycin therapy is begun during the first two trimesters . To more carefully delineate the gravidas who require treatment , Daffos et al. identified women who contracted toxoplasmosis during pregnancy and aggressively pursued the diagnosis in the fetus by culture of amniotic fluid and fetal blood in addition to serologic studies of the fetal blood . Of the 39 fetuses found to be infected , 24 were aborted at the request of the mother . The mothers of the rremaining 15 were treated with pyrimethamine and a sulfonamide in addition to spiramycin , and their pregnancies were allowed to continue to term. All of the infants survived and were followed for various periods between 3 and 30 months . Because all remained in good health , save for two who developed chorioretinitis , the authors concluded that it is practical to diagnose the disease in the fetus and , based on that , treatment can be provided that ?uces the severe manifestations of the disease. ?owever , after careful examination of their data and the findings of others , there appears to be less cause for enthusiasm . They failed to diagnose the disease in 3 fetuses . Of the 15 live - born infants , 4 had evidence of intracranial calcification at birth , and despite treatment , 2 others developed chorioretinitis during the follow - up periods . These 6 represent 40 % of the infants . There being no controls , it is dificult to know whether that reflects a benefit . If the 4 with intracranial calcifications and the other 60 % of infants remained without further evidence of illness , one might agree with the authors . The studies of others are worrisome because they indicate that serious problems may appear years after birth and despite treatment . Stagno et al ., in a follow - up study of eight infants with subclinical toxoplasmosis at birth , found that five developed chorio-retinitis , bilateral in three , between the ages of 3 month and 6 years .
Further information on the followup of infants with subclinical infection at birth is provided by Wilson et al., who studied 13 such infants and found 3 with unilateral blindness but bilateral disease and 5 with bilateral disease but minimal or no visual loss. The chorio-retinitis appeared earliest at 1 month of age and latest at 9.3 year ; 3 others suffered recurrences of active chorio-retinitis , which left only 2 unaffected . In addition to the visual problems , 1 of the 13 developed microcephalus , psycho -motor retardation , and at 5 years , seizures . Two others had mild cerebellar dysfunction , and an additional 2 had transiently delayed psychomotor function . Of the 13 , 10 had audiometric studies that revealed 1 each to have moderate bilateral, mild unilateral sensorineural hearing loss . They concluded that treatment from birth might have been of some help . Finally , Koppe et al. followed 11 infants with congenital disease for 20 years and found new lesions to appear in the eyes for as long as 18 years . Of 6 who had subclinical infection at birth and went untreated , 2 escaped without eye lesions , while none of the 5 who were treated escaped . Of the 11 patients , 9 ( 82 % ) suffered retinal scarring and disease in one or both eyes , 4 had severely impaired vision in one eye , and 3 had unilateral blindness . Ten other subjects with transiently elevated antibody titers at birth were considerd to be uninfected but also were followed . Four developed toxoplasmosis between the ages of 5 and 19 years , and 2 of them were found to have chorioretinitis . Evidently , some of the long - term problems may represent reinfection rather than progression or recurrence.
Little is known about the long - term effects of congenital toxoplasmosis on the CNS . Sever et al. studied 22,845 pregnant women from the Collaborative Perinatal Project and found a high - risk group of mothers based on Toxoplasma serologic data . A 7 - year follow - up of the offspring indicated that twice as many children of high - risk infected women were deaf than was expected from the controls , microcephaly was increased 60 % over expected , and IQ values of 70 or below were 30 % beyond expected . Unfortunately , from an epidemiologic point of view , the number of affected children was small . Texts contain the dogma that congenital toxoplasmosis results in seizures , mental retardation , and other manifestations of severe brain damage . There is little to prove that these consequences are anything but infrequent , if not rare , among congenitally infected infants . The available information is based on studies of very small numbers or investigations of questionable worth. For example , there is no evidence that intracranial calcifications found in radiographs of the skull shortly after birth indicate an unfavorable prognosis . # There are no follow - up data concerning infants with elevated values of cerebrospinal fluid protein concentration in association with serologic evidence of Toxoplasma infection . The confusion over the natural course of the disease is extended to include the matter of therapy . It seems that pregnant women who are diagnosed early and treated promptly have a better pregnancy outcome than do those who are untreated , but that is not based on multiple reports . In view of these inadequacies , it is not possible to intelligently deal with the problem .
Table No. 4 :- Eichenwald study of 152 infants with congenital Toxoplasmosis had following features
Neurologic manifestations 71 %
Chorioretinitis 95 %
Abnormal C.S.F. 55 %
Convulsions 50 %
Intracranial cakcification 50 %
Obstructive Hydrocephalus 28 %
Microcephaly 30 %
Mental retardation 80 %
Seizures 81 %
Motor defects 70 %
Hydrocephalus & / or Microcephaly 42 %
Deafness 16 %
Apperently normal 11 %
Table No. 5 : Two forms of congenital Toxoplasmosis is documented by Eichenwald :-
Generalised form Neurologic form
Chorio-retinitis 66 % 94 %
CSF - Pleocytosis & Protein elevation 84 % 55 %
Anemia 77 % 51 %
Convul-sions -- 50 %
Intracranial calcification -- 50 %
Jaundice 79 % 29 %
Hydro-cephalus -- 28 %
Fever 77 % 25 %
Spleno-megaly 90 % 21 %
Lymph-adenopathy 68 % 17 %
Hepato-megaly 77 % 17 %
Vomiiting 48 % 17 %
Micro-cephaly -- 13 %
Cataracts -- 4.6 %
Optic atrophy -- 1.9 %
Penumo-nitis 41 % --
Diagnosis :- Infants born of mothers known to have contracted toxoplasmosis during pregnancy are best served by studies of the placenta , blood obtained from the umbilical cord , and CSF of the infant . The organism can be isolated from the placenta by obtaining material to be stained for microscopic study and inoculation into mice or tissue culture media . The same can be done with umbilical cord blood and CSF . Infants who are infected may have spinal fluid pleocytosis and protein concentrations of 100 to 1,500 mg / dL .
Radiographs of the skull or sonographic studies of the head may demonstrate intracerebral calcifications . Of course , if they are present , cytomegalovirus infection must be considered and proper studies performed .
Serologic studies are imperative and are commonly the only basis for making a decision as to the status of the infant . The presence of specific Toxoplasma IgM antibodies in blood from the umbilical cord or the infant is diagnostic of congenital toxoplasmosis . But the converse is not true . It is unfortunate that specific IgM antibodies may not be evident in infected infants . The presence of specific IgM in the blood from the umbilical cord or infant at birth may be misleading if it represents the IgM of an infected mothr from a maternofetal transfusion that occurred shortly before parturition . In that case , the amount of antibody will fall prcipitously during the ensuing 5 to 10 days . The presence of a titer of specific Toxoplasma IgG antibody in blood from the umbilical cord or infant that is fourfold or more that of the mother is diagnostic of congenital toxoplasmosis . Unfortunately , circumstances arre usually not as clear - cut as the above , and in the absence of visual evidence of the tachyzoites , it is necessary to rely on more tenuous indirect information obtained from studies of the mother . The finding of very high titers of maternal serum IgG Toxoplasma antibodies ( Sabin - Feldman dye test, IgG IFA ) together with the presence of specific IgM antibodies at the time of the birth must be considered to represent a circumstance in which the infant is infected . Even if maternal - specific IgM antibodies are not demonstrable , it is less likely but still probable that the infant is infected .
Serologic studies of the CSF are inappropriate . However , repeated examinations of the fluid for tachyzoites , concentration of protein , and cell count is advisable .
It is imperative that all infants at risk of congenital toxoplasmosis or suspected of having it be folowed carefully by serial serologic evaluations done in conjunction with similar studies of the mother . In addition , it should be emphasixed that initial and serial funduscopic examinations be done by an ophthalmologist able to properly deal with infants and familiar with the appearance of toxoplasmosis of the retina in that age group .
Treatment :- There is no proven cure for toxoplasmosis . A limited number of agents have been applied but without an evaluation that gives confidence . Additionally , aside from the sulfonamides , none of the anti-microbials suggested have been studied with regard to their effectiveness or pharmacology in human newborn infants . The sulfonamides displace indirect acting
( unconjugated ) bilirubin from serum albumin , thereby subjecting the infant to the risk of kernicterus . Accordingly , their use should be delayed until there is no evidence of increased serum concentrations of bilirubin .
Despite the above negatives , it is more reasonable to treat than not to treat under certain conditions .
1. Courveur?regimen recomm-ended by Remington and Desmonts for the treatment of newborn infants with congenital toxoplasmosis includes a 21 - day course of 1 mg pyrimethamine per kilogram of body weight orally once every 1 to 4 days ( preferably every 3 - 4 days ) together with 25 to 50 mg sulfadiazine per kilogram of body weight orally twice each day ( triple sulfonamides may be substituted ) .
2. This is to be followed by a 30 to 45 days course of 50 mg spiramycin per kilogram of body weight orally twice each day . These periods of antimicrobial therapy should be alternated for a year . Spiramycin is not approved for use in the United states , but can be obtained from the Centers for Disease Control on request.
3. Because pyrimethamine is a folic acid antagonist , 5 mg folinic acid should be provided orally twice each week while it is being used .
4. For those infants with high concentrations of protein in their CSF or active chorioretinitis , it is suggested that 1 mg prednisone per kilogram of body weight be given orally twice each day until the active retinal inflammation is resolved or the elevated values of CSF protein are no longer present .
The initital problem in the treatment of congenital toxoplasmosis is the matter of case selection .
Indications for treatment :-
1. Newborn infants with overt Toxoplasma infection .
2. Active chorioretinintis .
3. Elevated concentrations of CSF protein.
4. Infants known to be infected but with out clinical evidence also are included among those to be treated according to the regimen described.
5. Then there are the apparently healthy infants with equivocal laboratory findings and uncertain historical information . If the mother is known to have contracted toxoplasmosis during the pregnancy and the newborn infant lacks clinical or laboratory evidence of the disease , one cycle of pyrimethamine with sulfadiazine and folinic acid followed by spiramycin is suggested while further investigation is carried out to learn more about the mother and her infant .
6. With the use of the toxoplasmosis - specific IgM immunosorbent agglutination assay , it is hoped that there will be fewer serologically confusing cases . Nevertheless , there are circum-stances in which confusion , inadequate information , and questionable data do not allow a reasoned decision to be made . Under these conditions , a judgement is made in which one usually tends to err on the side of providing treatment .
Guidelines - 4 :- ( For treatment of paediatric patients - )
1. Sulfadiazine 100 mg / kg / day and pyrimethamine 1mgm / kg / day given twice a week.
2. Folinic acid 5 mgm is given twice a week .
3. Alternated with Spiramycin 100 mgm / kg / day , given in 6 weeks cycles.
4. Therapy for small children consists of Sufadiazine or Trisulfapyrimidine ( 150 mg / kg / day in divided doses ) , and Pyrimethamine ( 1 mgm / kg / day in divided doses ) .
5. A double dose is used for the first 3 days.
6. Prednisolone , 1 - 2 mgm / kg / day , should be added to the therapy in newborns with a high protein concentration in the C.S.F. or chorioretinitis.
7. Treatment should be continued for 6 months for both congenital and acquired Toxoplasmosis .
Abstracts :-
1.Toxoplasmosis of in Women of Child Bearing Age and Infant Followup After In-utero treatment .
P.Chakraborty , Sukanta Sinha et. al. , Indian Journal of Paediatrics , 1997 ; Nov - Dec : 64 : 879 - 882 .
A total of 540 women ( including 70 pregnant cases ) of child bearing age with bad obstertrical history were tested serologically for anti - toxoplasma antibody using microlatex agglutination test . Forty two women including 5 cases of pregnancy were found to be seropositive in a titre of 1 : 32 or more . Maximum prevalence ( 10.2 % ) and highest titer of anti - toxoplasma antibodies were observed in women of 35 - 42 years age group. The overall prevalence of toxoplasmosis in these women was 7.7 % , wherease it was 7.1 % in pregnant women . Further studies are needed to estimate the exact rate of prevalence of infection . Of the 70 pregnant women , 5 were seropositive and two of them acquired infection during pregnancy which was detected by IgM immunososrbent assay . Seropositive pregnant women were treated using combined regimen of sulfadiazine and pyrimethamine . Four infected women with pregnancy were followed up and one didnot turn up subsequently . There was spontaneous abortion in one case and in 3 other cases full term normal babies were delivered . Incidence of toxoplasmosis in women is low because of infreqent and uncommon practices of ingesting undercooked or uncooked food stuff specially meat by a substantial number of the population surveyed .
2. Cholestatic Jaundice Due to Congenital Toxoplasma Gondii Infection .
S. Singh, Rakesh Lodha et.al. AIIMS,New Delhi , Indian Journal Of Pediatric 1998 , Jan - Feb. ,65 : 154 - 157 .
A case of congenital toxoplasmosis manifesting as hepatosplenomegaly and chole -static jaundice in a 4 month od child is reported . To the best of our knowledge this is the first report of cholestatic jaundice due to congenital toxoplasmosis from India . The child was successfully treated with sulphadiazine & pyremethamine combination .
3. Status of Toxoplasma Antibodies in Recurrent Fetal Loss in U.A.E. Women .
Nishi Singh , Indian Journal of Pediatric , Nov - Dec 1998 ; 65 : 891 - 897 .
A retrospective analysis to determine the status of toxoplasma ( IgG & IgM ) antibodies in UAE women with recurrent fetal loss was done using immunofluorescence assay . Two thousand three hundred and fourty three patients with one or more fetal loss were studied over a period of five years .
In patients with fetal loss , the range of toxoplasma IgG seropositivity varied from 24.2 - 30.6 % . There were 3 patients with IgM positive . Only in a single patient one of her two abortions could be altributed to acute toxoplasmosis .
Habitual fetal loss cannot be attributed to chronic toxoplasmosis. Also , 67.2 % of the women of child bearing age group in U.A.E. were found to be seronegative , highlighting the need for routine antenatal screening to detect primary acute toxoplasmosis .
The extent to which Toxoplasmosis causes habtual abortion is still controversial . In a study carried out in Egypt on 100 cases of repeated abortions , 19 % of the cases and 7.5 % of the controls were seropositive for Ig M . The difference was statistically insignificant and the authors concluded that acute Toxoplasmosis is not related to habitual abortions. However , 37 % of cases and only 10 % of the controls were seropositive at high dilution for Ig G ; this statistically significant difference may indicate that chronic Toxoplasmosis may be a significant cause of repeated abortions.
No well documented report of fetal infection occuring in chronically infected mothers has appeared except for the study of 100 cases of repeated abortions by Sahwi and colleagues. Therefore , recurrent fetal loss cannot be attributed to chronic Toxoplasmosis.
Identification of fetal infection by Toxoplasma is a diffult task , Amniocentesis & cordocentesis , both have beeb applied and tests were carried out by Ig M assay on amniotic fluid and cord blood and animal inoculation studies ( albinomice intraperitoneal inoculation for isolation of organisms ) . Animal inoculation appears to give better results as regards the isolation of organisms and confirmatory diagnosis . It appears that isolation of parasite from fetal blood is more sensitive than determination of the antibody status , possibly because Ig M is not always produced by midgestation.
Referrences :-
1. Avron Y. Sweet , Edwin G. Brown , Fetal and Neonatal Effects of Maternal Disease, Pg 191 - 201.
2. Bruce O. Berg , Principles of Child Neurology , International Edition ; Pg 830 - 833.
3. Gerald M. Fenichel , Clinical Paediatric Neurology, 3rd edition, Pg 122 - 123.
4. John H. Menkes , Text Book of Child Neurology , 3rd edition , Pg : 353 - 356.
5. Nishi Singh , Status of Toxoplasma Antibodies in Recurrent Fetal Loss in U.A.E. Women , Indian Journal of Paediatrics , 1998 , Nov.- Dec. , 65 : 891 - 897.
6. P. Chakraborty , Sukanta Sinha , , Toxoplasmosis in Women of Child Bearing Age Infant Followup After In Utero Treatment , Indian Journal of Paediatrics , Nov. - Dec. 1997 ; 64 : 879 - 882.
7. S.Singh, Rakesh Lodha et.al., Cholestatic Jaundice Due to Congenital Toxoplasma Gondii Infection, Indian Journal of Paediatrics , Jan. - Feb. 1998 ; 65 : 154 - 157.
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