TOXOPLASMOSIS: A PREVENTABLE CAUSE OF BRAIN DAMAGE Neil Gordotr

Infection with the protozoan Toxoplasma gondii can be either congenital or acquired. I t is an obligatory intracellular parasite in a wide range of birds and small mammals, but man has no part in the life- cycle. 30 to 80 per cent of domestic cats are infected'. Humans may become infected by transmission of the organism from the mother to the fetus iri ictero, by ingesting oocysts in uncooked meat or by contamination by cat faeces, for example through unwashed hands, particularly after contact with cats or affected soil. As a result, high rates of infection occur when uncooked meat is often eaten, and there is a high density of domestic cats and other intermediate hosts, when survival of the oocysts is more likely. Very rarely the disease can be transmitted by organ transplant, and laboratory workers are at increased risk.

The organism enters the cystic phase in response to antibodies formed by the host. When the asexual cycle occurs in man, the tachyzoite enters nucleated cells to form pseudocysts in the acute stage, and bradyzoites which form tissue cysts in the chronic stage. Encysted toxoplasma are resistant to gastric pepsin, but they are killed by freezing. Exposure to antibody, and a heat-labile serum activity usually called 'activator'? destroys the surround- ing membrane of the trophozoite when

they are used together; and the organism dies.

The incidence of toxoplasmosis varies greatly between countries; as determined by serological testing, in France about 80 to 85 per cent of the population are infected by the age of 20, while among Eskimos there is no evidence of this disease. In the UK and USA about 20 per cent are infected by the age of 203. In Paris and its suburbs, where many are of low socio-economic status, about 10 pregnant women per 1000 per year acquire toxoplasmosis4; and there can be no doubt that toxoplasmosis can cause serious disorders of a number of tissues. This is particularly so in congenital infections, and among immunocom- promised patients'.

Acquired infection The incidence of infection in pregnant women depends on the prevalence of Toxoplasma gondii in the environment, the frequency of contact with one of the sources of the parasite, and the number of women in the community who have not previously developed immunity as a consequence of previous infection. First the placenta is involved, and then the fetus.

Most postnatal infections are symptom- less, or are mild and go unrecognised, because of the acquisition from animal sources of the parasites, which are not 567

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adapted to or have a low intrinsic pathology for man, or because of high host-resistance. In fact, a high percentage of adults show evidence of previous infection on serological testing.

When there is evident toxoplasmosis infection, the most common presentation is an illness which simulates glandular fever, although the Paul-Bunnell test is negative. The incubation period is seven to 17 days, and the lymphadenopathy, most frequently involving the posterior cervical glands, may or may not be associated with fever, headache and a sore throat. There may also be arthralgia, and an urticaria1 or maculopapular rash. In England and Wales, between 1976 and 1980, i t has been estimated that 27.5 per cent of newly reported cases of toxo- plasmosis present in this way3, and that 15 per cent of patients with unexplained glandular enlargements are suffering from toxoplasmosis6. Antibody concen- trations are high in the glandular form but lower in the ocular and other late-onset forms. In England and Wales, the ma1e:female ratio for acquired toxoplas- mosis during childhood is 3:1, while among adolescents i t is 1: l and among adults it is l : 3 3 .

Other forms of the disease include encephalitis, a typhus-like illness, pul- monary infection, myocarditis, hepatitis, uveitis and a schizophrenic form of psychosis. The white blood counts can be normal or reduced, and the liver and spleen may be enlarged. Toxoplasma are recovered from all kinds of tissue: blood, CSF, brain, liver, spleen, heart muscle, lymph nodes and eyes’.

Initnunostcppression and f oxoplasnrosis Recrudescence of a latent infection in the presence of immunosuppression, including AIDS, has been well recorded’. s. Cerebral abscesses and cncephalitis-which can be fatal-have been reported, although toxo- plasma encephalitis is usually subacute, with headache, fever, mild hemiparesis, a confusional \[ate and focal seizures. Movement disorders are rare, in spite of basal ganglia lesions. Most cerebro- vascular lesions due to toxoplasmosis in patients with AIDS result from cerebral infarction, often secondary to non- bacterial thrombolytic endocarditis or

disseminated intravascular coagulopathy. Such opportunistic infection can also occur in patients with leukaemia, aplastic anaemia, Burkitt’s lymphoma and after allogeneic bone marrow transplants. Sometimes, especially in infants with encephalitis, it can be difficult to know whether it is a primary infection or whether there is an underlying disease, so it may be justifiable to carry out tests for toxoplasmosis in all cases of encephalitis of uncertain origin8. On CT scanning, toxoplasma encephalitis usually shows ring-enhancing lesions, compatible with focal signs, and occasionally petechial haemorrhages are seen in toxoplasma abscesses. Neuroradiological monitoring may be indicated for patients with AIDS who have a high immunoglobulin G toxoplasma titre; and also consideration of prophylactic treatment’.

Serological tests may be negative, although detection of IgA antibodies may prove valuable in the diagnosis of acute infections. I t may be necessary to t ry to identify toxoplasma from biopsy material. I f the diagnosis is urgent, as in the case of an immunological deficienr host or preg- nant woman, KRICK and REMINGTON6 suggest that the criteria for diagnosis should not be too stringent, so that specific therapy can be started immediately; for example a conventional indirect fluorescent-antibody or dye test titre of 1:1000, with a negative IgM indirect fluorescent-antibody titre, may be sufficient.

Congenital infections Studies in the USA have shown an incidence of congenital infection ranging from 1 : 1000 to I :8000 live births’, and if stillbirths are included, some of which may be caused by toxoplasmosis, this incidence increases’. However, there are insufficient recent data definitely to determine this, and the incidence varies greatly from place to place.

Only newly acquired infection in preg- nancy seems to endanger the fetus. Toxoplasma lesions can develop in the placenta, and have been isolated from the placentas of 25 per cent of those who have acquired the infection during pregnancy. The organism can then gain entry to the fetal circulation’. Fetal infections before

the second month of pregnancy are often lnore severe than those which occur later on, but are not so common. Infection acquired in the third trimester usually results only in subclinical disease, which remains latent for the first few years of life, while infection in early pregnancy may well result in a stillbirth. Symptoms may occur at birth, or be delayed for a few days or weeks. Once infection has been acquired in this way there is practically no risk to subsequent children because of the mother's antibodies, except among pregnant women who are inmmunocompromised.

The manifestations of congenital toso- plasmosis include chorioretinitis (often bilateral), cerebral calcification, mental retardation, convulsions, microphthalmia. hydrocephalus and microcephaly6; the range being from asymptomatic to still- birth. Among other findings are hepato- megaly (sometimes with jaundice), splenomegaly, anaemia and a maculo- papular rash; findings not unlike those of haemolytic disease of the newborn infant. In addition, signs of cerebral palsy and encephalitis can develop days or months after birth3. The CSF may be abnormal, even in subclinical infections, with increased protein and cell count. As mentioned, these findings, compatible with more severe disease, are only likely to occur after infection in early pregnancy. Chorioretinitis and neurological symptoms may not be present at birth, but may appear later in infancy or childhood; in such instances the condition may be less severe, but i t can progress. Chorioretinitis, when present during the first year of life, correlates with a low IQ'O.

I f maternal antibodies reach high titres before the baby is born, they will cross the placenta and modify the disease, elimin- ating the parasites from most tissues". I f antibodies are formed some time before parturition, the infection is likely to be suppressed in all tissues, except the brain and retina.

I t is suggested that toxoplasmosis plays a role in producing congenital brain lesions. An analysis was made of the frequency of toxoplasmosis between 300 normal children and 266 with congenital brain lesions in similar age-groups. In all age-groups, the higher frequency of

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tosoplasmosis infection in children with congenital brain lesions was statistically significant, seeming to prove that a form of congenital toxoplasmosis with very few symptoms exists and contributes to the genesis of such brain lesions".

DESMONTS and COUVREUR" r2viewed y1

378 pregnant women, living in Paris, who had high initial toxoplasma antibody - titres or seroconversion during pregnancy. 2 The infection was acquired during 2 pregnancy by 183 mothers (6 .3 per cent of 3 the pregnancies), there were 1 1 abortions 3

2 and seven babies were stillborn or died. Toxoplasmosis occurred in 59 of the non- aborted offspring, of whom two died, seven had severe disease with cerebral and ocular involvement, 1 1 had mild and 39

FELDMAN" selected 101 patients from various parts of the world on the basis of positive dye test findings in the serum, and carried out a retrospective study- with the disadvantages this entails. Of 191 patients with chorioretinitis, 48 per cent had congenital toxoplasmosis; and of 11 5 with cerebral calcification, 50 per cent had this disease. No congenital anomalies were noted among 46 children with congenital tosoplasmosis. The mothers reported no illnesses during pregnancy in 85 per cent of the cases. Exposure to animals during pregnancy was recorded by 71 per cent and denied by 29 per cent.

SAXON and colleagues" studied the intellectual and social development of eight children aged two to four years who were identified at birth as having con- genital toxoplasmosis, and compared them with eight controls. The results suggest that subclinical toxoplasmosis may have an adverse effect on intellectual development, and that early treatment may be of preventative value.

Ocular and auditory disease is common among infants born with congenital toxoplasmosis. Most are undoubtedly asymptomatic in the newborn period, and therefore their infection goes unrecog- nised. WILSON and colleague^'^ followed up 23 such children whose average age at last examination was 8'/2 years. They were divided into two groups: in the first (N = 13) the diagnosis was made prospectively, and in the second ( N = 10) no symptoms or signs were noted during the newborn period.

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and the diagnosis was made only after the first symptoms were noted. 11 of the first group, and all of the second, developed chorioretinitis. The incidence of unilateral blindness was 23 (three children) and 27 (three children) per cent, respectively, while 45 per cent (five children) of the second group showed bilateral blindness. One child in group 1, and two in group 2, developed severe nedrological sequelae after presenting with eye disease. Occasional hearing deficits were found in both groups. W~LLIAMSON et al.I6, in their series, found that 1 1 of 17 patients had sensorineural hearing loss, in three of whom it was progressive. Learning dis- abilities were identified in four children with hearing loss and normal intelligence. Developmental verbal dyspraxia was recorded in two children.

Although uveitis due to toxoplasmosis can occur in the acquired form, it is more often of congenital origin, particularly when cysts are reactivated as antibodies decrease. Only a complete absence of antibodies excludes the diagnosis of tosoplasma uveitis.

Other ocular complications include ocular nystagmus, strabismus, cataract, optic atrophy, iridocyclitis and glaucoma’.

Radiological findings Toxoplasma lesions in the brain and eye start as vasculitis, followed by necrosis and cellular infiltration in the cortex, meninges, white matter, basal ganglia, brainstem and spinal cord. As necrosis progresses, calcium is deposited: these deposits are either nodular, curvilinear or in the form of multiple flakes. A combination of the first two is said to be pathognomonic of toxoplasmosis17. The diagnosis is from torulosis, histoplasmosis, blastomycosis, cysticercosis, trichinosis, haemolytic disease of the newborn infant and tuberous sclerosis. In toxoplasmosis the deposits are best seen in the ependymal and subependymal regions, in the choroid plexus and caudate nucleus, and in the meninges, when frontal and semi-axial views are taken. Calcification in the meninges and caudate nucleus is seen only in young children who die early or have a poor prognosis. Toxoplasmosis must be considered as a frequent cause of

cerebral calcification in x-rays of the skull, and on CT scanning.

Pathological findings Those in the newborn infant are well described by HALL et af . ’* , in their report of two babies dying of congenital toxo- plasmosis: one lived for only a few minutes and the other died after several months with hydrocephalus, chorio- retinitis, microphthalmia and cerebral calci- fication. Many tissues were examined, including the brain: pseudocysts were found in the brain of the first infant, and toxoplasma in various tissues of the other. Both had rashes, and it is suggested that liver damage may be a major aetiological factor for this; liver damage, as in haemolytic disease of the newborn infant, can also be a result of iso-immunisation. The placenta of the second patient showed evidence of damage and the presence of toxoplasma, but its increased size was due to oedema and not to structural changes.

Lesions are most frequent in the cerebellum adjacent to the fourth ventricle, the ependyma of the aqueduct and the choroid plexuses of the eyes”. Large granulomatous areas with necrotic centres can occur, as well as diffuse inflammation and small miliary granulomata; the latter are most common in the cortex, and consist of large epithelioid and round cells. Organisms can be found free in the most recent lesions and in the subarachnoid space. Hydrocephalus is most often caused by ependymitis involving the aqueduct.

Diagnosis In toxoplasmosis there can occur increased protein and cells in the CSF, and increased oligoclonal immunoglobulins in both the serum and CSF of those with con- genital toxoplasmosis. The diagnosis of toxoplasmosis is usually made by serological tests measuring IgG- or IgM- specific antibody. The former includes the Sabin-Feldman dye test-the most commonly used-and the immuno- fluorescent antibody test; the latter the IgM-immunofluorescent antibody test, and the IgM-enzyme-linked immuno- sorbent assay. The last is the most reliable”. The dye test results are a

measure of the dilution at which 50 per cent of the parasites remain unstained after incubation in serum, and dye.

In a study of pregnant women in Paris, Desmonts and Couvreur" found that rising titres of a modified dye test appear within two months of infection and persist for several years, gradually de- clining to around 1:50. A high proportion of healthy people have a positive dye test. I f the titres are high, the test is diagnostic i f Ighl is also present; but when using the [gbt-fluorescent antibody test, absent IgM does not exclude the diagnosis in con- genital toxoplasmosis". The complement fixation test is not positive for several weeks after the dye test, and remains positive for a shorter period. Antibody levels in the fluorescent antibody test are generally parallel to those with the dye test. There is also a dermal sensitivity test, which becomes positive several months after infection and may remain so for life.

Trophozoites can be isolated from the blood and CSF, or from tissue biopsies, by animal inoculation, and then isolation in tissue culture6. In addition, toxoplasma can be identified in lymph node biopsies by immunofluorescence, but techniques such as these are used mainly for research.

The differential diagnosis of tosoplas- mosis is from such conditions as glandular fever, infections with Epstein-Barr virus and cytomegalovirus, brucellosis, lepto- spirosis, glandular tuberculosis, lymph- oma, Hodgkin's disease and leukaemia3.

The diagnosis of recent maternal primary infection is based on serocon- version, or a marked increase in the titre of antibodies over several weeks. To be certain of diagnosing such infection during pregnancy, IgM should be measured every few weeks to detect a rising titre, since this may be an indication for chemotherapy. High antibody levels, two tube-dilutions above significant titres-1:4096 for indirect fluorescent antibody, indirect haemagglutination and the dye test, and 1:32 for complement fixation-strongly suggest recent or present infection with Toxoplasma gondii2*. I f the history is suggestive, placental tissue should be subjected to animal inoculation.

Radiological findings, such as intra- cranial calcification, and the use of ultra- sound to show cerebral lesions can help in

the diagnosis of established disease.

Prevention and trealnietrt Prevention is obviously of great impor- tance, especially during pregnancy. I f there are cats in the household, they should be prevented from eating infected mice (but this easier said than done), hands should be washed after handling them. especially before eating, their litter trays should be emptied daily-not by the pregnant woman-as oocytes take t w o or three days to become infectious, and they should not be fed with raw meat products". Preventative screening of mothers with serological tests is questionable; education of mothers seems a more practical policy".

Drugs of proven value in the treatment of toxoplasmosis are the sulphonamides and pyrimethamine. They can eliminate trophozoites, but not encysted forms. As the disease can be progressive, treatment should be given as early as possible; and in view of the evidence of possible long- term brain damage, treatment is justified even in the absence of symptoms1'.

The treatment of infected infants and very young children consists of sulpha- diazine 100 to 150mg/kg/day in divided doses, and pyrimethamine lmg/kg twice a week to Img/kg daily in divided doses, a double dose being used for the first three days. Folinic acid is also given, 5mg twice a week, as pyrimethamine is a folic acid antagonist. This regime can be alternated with spiramycin 100mg/kg/day, given in six-week cycles. For older children and adults the usual dose of sulphadiazine is up to a maximum of 4g/day, with 25mg of pyrimethamine and 5 to 1Omg of folinic acid. Platelet and white cell counts should be performed twice weekly, and the drugs should be stopped if either are significantly reduced. Treatment is con- tinued for six months in congenital infections, and for a year in acquired infections3. Pyrimethamine is best avoided during the first trimester of pregnancy because of its possible teratogenicity and, especially in AIDS, sulphadiazine can cause renal impairment due to crystal formation.

All mothers with confirmed acute infections should be treated, particularly i f the pregnancy is to be continued, since treating the mother during pregnancy is a

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way of treating the fetus. DAFFOS et alSz3 studied 39 fetuses, diagnosed antenatally: 24 of the pregnancies were terminated and 15 continued. All the mothers were treated with spiramycin throughout preg- nancy, and if fetal infection was demon- strated, pyrimethamine and a sulphon- amide were added. Of the 15 fetuses with congenital toxoplasmosis who were carried to term, all but two who had chorioretinitis remained well during a follow-up of at least three months, con- firming that such prenatal treatment is effective.

All those with acute chorioretinitis and other ocular manifestations should also be treated; and apart from treating acute infections, there is a case for considering chemotherapy for all immunosuppressed people, as well as those awaiting bone marrow transplants if there is evidence of previous toxoplasma infection3. Atova- quone seems to be effective in treating toxoplasmosis in patients with AIDS, who are intolerant of other therapiesz4. Infants infected in irtero may need three or four courses of treatment in the first year of life, and babies with subclinical infections also should be treated since this can prevent brain damage”.

The results of treatment are encour- aging, and seem to justify following these suggested drug regimes. However, better controlled clinical trials are needed before more dogmatic recommendations can be made.

Conclusion There is no doubt that toxoplasmosis can cause significant morbidity, much of which is preventable. It is a common infection, and most people are clinically unaffected. However, acquired infection with Toxoplasma gondii may result in illness varying from one resembling glandular fever to a fatal encephalitis. Those who are immunosuppressed are at particular risk. Pregnant women must be given special consideration, in view of the possible danger to the unborn child: congenital infection can cause damage to a variety of tissues, particularly the brain, and stillbirth can occur. The brain damage may result in cerebral palsy, mental retardation and epilepsy. Pre- vention can be effective if those at risk are

taught how to avoid infection, so this should be part of health education. Drug treatment of those with the disease should be commenced as soon as the diagnosis is made, but is a matter of particular urgency for pregnant women and immunosuppressed patients.

In a review of congenital toxoplasmosis, HALL” cor,siders the pros and cons of prenatal screening. The arguments against introducing a national programme in the UK (as recommended by a multidisci- plinary working group of the Royal College of Obstetricians and Gynaecolo- gists, 1992) are persuasive; they include infection of the fetus before the test is done, and termination of the pregnancy when the fetus is normal. The distress experienced by a mother with toxoplas- mosis who loses a normal fetus as the result of tests is well described in the British Medical Journal (April 20th, 1991, p. 973). In addition, the efficacy of testing the mother early in pregnancy is based on the theory that only maternal infection acquired for the first time after conception places the fetus at risk, which is not always true.

Toxoplasmosis is of world-wide distri- bution, so should not be regarded as a medical curiosity’. The introduction of a national prenatal screening programme would need an extensive health service infrastructure, including adequate 1abor:r- tory and counselling services; and bcforc further decisions are made, a largc, multicentre trial would be useful26. Thc Toxoplasmosis Trust o f 61-71 Collier Street, London, will provide help to families in the UK with a child suffering from congenital toxoplasmosis.

Accepted for publication 26th November 1992.

Correspondence lo Dr. N. Gordon, Huntlywood. 3 S ~ y a l Road, Wilmslow. Cheshire SK9 3AE.

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