Central nervous system toxoplasmosis in acquired immunodeficiency syndrome : An emerging disease in India.
With the incidence of patients infected with human immuno-deficiency virus (HIV) increasing in India, the central nervous system (CNS) manifestations of the disease will be seen more frequently. The CNS may be primarily afflicted by the virus or by opportunistic infections and neoplasms secondary to the immune suppression caused by the virus. In India, although mycobacterium tuberculosis has been reported to be the most common opportunistic infection, toxoplasmosis may become as common owing to the ubiquitous nature of the protozoan. Since an empirical trial of medical therapy without histopathological diagnosis is recommended, the true incidence of this condition may remain under estimated. The role of ancillary tests such as radiology and serology in the initial diagnosis of this condition remain crucial. This report highlights two patients who were diagnosed to have acquired immuno-deficiency syndrome (AIDS) only after the biopsy of the intracranial lesion was reported as toxoplasmosis. Presently all patients for elective neurosurgery are tested for HIV antigen. The management protocol to be followed in a known patient with AIDS presenting with CNS symptoms is discussed in detail. The value of ancillary tests is also reviewed.
World health organization (WHO) estimates that there are over 1.75 million human immuno-deficiency virus (HIV) infected adults throughout India and that by the turn of the century it will have more cases of acquired immuno-deficiency syndrome (AIDS) than any other in the world. The dominant mode of spread of HIV in India is by inappropriate heterosexual behaviour, followed by transmission through infected blood and blood products. Intravenous drug users play a major role in HIV transmission in the North-eastern state of Manipur.
The core groups involved in the dissemination of AIDS, are commercial sex workers (CSW) and professional blood donors. The seroprevalence among the CSW has shown an increase over the years and is about 25-40%. The seroprevalence among patients attending sexually transmitted disease (STD) clinics has risen to 5-11% in select cities and 1.6% nationwide, with a seroincidence of 10.2% per year. In India, paid donors form about half of all blood donors. These donors have frequent contact with CSW and history of STD. In Mumbai, it was found that 90% of blood donors had donated blood regularly for more than 5 years. Of these 86% were HIV positive, and 48% still donated blood despite being infected with HIV. The first reported case from India was in May 1986 and by the end of 1994 only 712 cases of AIDS had been officially reported. This under-reporting is due to lack of clinical suspicion, case definition, and facilities for serological testing.
In India, tuberculosis is reported to be the most common opportunistic infection in HIV infected individuals. An autopsy study from Mumbai has shown that 13 of 15 AIDS cases had a culture positive mycobacterium tuberculosis. In Pune about 6.5% of HIV patients had evidence of active tuberculosis. Among these, 60% had evidence of extrapulmonary disease. Though studies have found the sero-prevalence of toxoplasmosis to be about 30-60% in the general population, only few cases of CNS toxoplasmosis have been reported in literature., The true incidence of CNS toxoplasmosis may not be forthcoming, as empirical drug therapy is a standard practice for patients with intracranial mass lesions.
We report two patients who were initially diagnosed to have multiple abscesses and/or granuloma. CNS toxoplasmosis was not suspected and surgical treatment was undertaken. After biopsy was reported as toxoplasmosis, it was found that both patients were positive for HIV antigen. Anti-toxoplasma drugs were started, but both succumbed to the disease within a week of the diagnosis.
Case 1 : A 42 year old diabetic male, controlled on medication, presented with fever, progressive left sided weakness, speech difficulty and raised intracranial pressure of 2 weeks duration. He was a heterosexual with history of multiple sexual partners. On examination he was opening eyes to pain and localized painful stimulus (GCS 9/15). He had left hemiparesis with early papilloedema. He was admitted in another hospital, and following a computed tomography (CT) scan, a diagnosis of multiple intracranial abscesses was made. He was empirically started on steroids and antibiotics. However, his clinical condition worsened and he was referred to us for stereotactic biopsy and definitive diagnosis.
Blood investigations were normal but ELISA and Western blot tests done after the biopsy were positive for HIV antigen. CT scan showed multiple hypodense lesions with significant perilesional oedema. With contrast there was peripheral rim enhancement [Figure la] [Figure lb]. Magnetic resonance imaging (MRI) of the brain showed multiple ring enhancing lesions in both frontol-parietal regions and the cerebellum [Figure 2]. He underwent a CT guided stereotactic biopsy (STB) of the lesion which was reported as toxoplasmosis. Post STB scan did not show any haematoma at the site of biopsy. Though he was started on adequate dosage of sulphadiazine and clindamycin, his clinical condition continued to deteriorate and he died on the 3rd day following biopsy.
Case 2 : H.M, 50 year old male presented with low grade fever and vomiting of 4 days duration followed by weakness of the right upper and lower limbs. There was no history of alteration of sensorium, seizures, or any cranial nerve involvement. He had exposure to multiple heterosexual partners. He was diagnosed to have pulmonary tuberculosis in a local hospital few months back, based on intermittent fever and loss of weight, and was started on anti-tuberculous therapy (ATT). Systemic examination was unremarkable except for a chancre on the penis. He was conscious, oriented and had normal language functions. Fundus showed papilloedema. He had right side hemiparesis with neck stiffness. CT scan showed an ill defined hypodense lesion in the left basifrontal region, close to the falx, with marked white matter oedema and mass effect. There was no appreciable contrast enhancement seen [Figure 3]. Chest X-ray and blood tests were normal. He underwent left frontal craniotomy and excision of the mass. The biopsy was reported as necrotizing chronic inflammation consistent with toxoplasmosis. Blood sent for HIV antigen was reported positive. He was started on sulfadiazine and pyrimethamine. On the 5th day, he developed high grade fever and his sensorium began to deteriorate. A repeat scan did not show any heamatoma at the site of surgery. There were no new lesions as well. His condition deteriorated progressively and he expired on the 7th post operative day.
In prospective studies it has been shown that about 50-63% of patients diagnosed to have AIDS present with involvement of the CNS; and about 10-20% of the patients have neurological features as the primary manifestation of the disease. Autopsy studies, however, show that more than 90% of patients have evidence of neurological dysfunction, but most tend to be overlooked. This leads us to recommend routine testing for HIV antigen before elective neurosurgical operations. This will especially be applicable to those patients who have been operated and or transfused blood and those with unusual image findings.
In addition to the direct effects of the virus on the CNS, there are lesions that occur secondary to the virus induced immune suppression. These are the opportunistic viral and non-viral infections and tumours. About 10% of AIDS patients develop a CNS mass lesion and the common causes of these lesions causing focal neurological deficits are toxoplasma encephalitis, followed in frequency by lymphoma. The less common lesions are pyogenic abscess, tuberculosis, fungal abscesses, and vascular lesions. The common non mass producing lesions are progressive multifocal leukoencephalopathy (PML), HIV-1 encephalitis and cytomegalovirus infection. Patients with AIDS also have a high incidence of multiple intracranial pathologies occurring either separately or concomitantly.,,
Toxoplasmosis is caused by the intracellular protozoan Toxoplasma gondii. The three forms of the parasite are the trophozoite, cyst and oocyst. The trophozoites are responsible for the acute infection and the cysts are present in multiple organs in the latent form. The human beings acquire the infection by ingestion of the oocyst, the ingestion of poorly cooked infected meat, and by congenital infection in utero. T. gondii, like other opportunistic pathogens, has a high prevalence rate in many populated groups and is capable of living in multiple tissues for the entire life of its host. Though there are no large epidemiological data on the serological prevalence of toxoplasmosis, a few studies indicate that about 30-60% of the population is seropositive.,
Unlike the western literature, where toxoplasmosis has been reported as common cause for intracranial mass lesions, only a few cases have been reported in the Indian literature., All these were enhancing solitary lesions that were diagnosed based on the radiological and serological data and an apparent cure achieved with anti toxoplasma drugs. The paucity of clinical cases detected may be because of lack of clinical suspicion or underreporting of cases, especially since many are started on anti-toxoplasmosis agents without any histopathological evidence.
Value of serological tests : Various serological tests are used to detect antibodies to T.gondii infection. Anti-toxoplasma immunoglobulin M (IgM) titers usually rise during the acute phase of the infection and fall within a few months. As encephalitis is usually due to reactivation of latent infection, this antibody response may not be seen., It has even been found negative in patients with confirmed cerebral toxoplasmosis. The serum IgG antibodies rise gradually over a period, after the initial infection. A four fold increase in the IgG titers from the baseline value is indicative of active infection. However, this increase in titer may be seen in only a small subset of immuno-suppressed patients. It is recommended by some authors that IgG values be routinely measured at the time of initial diagnosis of AIDS to serve as baseline for future estimations.,,
The serological tests are of limited use in clinical diagnosis owing to the high seronegativity (16%-22%) in IgG titers in patients confirmed to have CNS toxoplasmosis. The high prevalence of anti-toxoplasma titers in the general population compounds the problem.14,16 These tests, prove to be useful when the non detection of IgG titers along with single lesion in the radiological studies may indicate the need for an histopathological diagnosis before initiating treatment. A negative serological test should not be used to exclude the diagnosis of toxoplasmosis in patients with AIDS., Radiological Criteria : CT scan shows multiple, bilateral, hypodense lesions which enhance in the periphery with contrast. Porter et al have found only 10% of lesions to be non enhancing on a CT scan. Among the rest, 82% were peripherally enhancing. The lack of contrast enhancement may be due to the paucity of inflammation or less vigorous peripheral vascular proliferation. The median number of lesions detected in a CT scan was 2 and in about 27% of patients the lesion was solitary.
MRI is more sensitive than CT in detecting these lesions. It shows more lesions and it often reveals lesions not detected on a CT scan. MRI detects both the old and the new lesions and without contrast enhancement or perilesional oedema cannot differentiate between the two. On the T1 weighted images the hypodense areas represent the active lesions and these usually enhance with contrast. In the T2 weighted images they are of variable signal intensity and may represent lesions of different age. Ciricillo et al in an earlier study had reported that 71% of solitary lesions visualised in an MRI represented primary CNS lymphoma and only about 18% of these were toxoplasmosis. Subsequently, after reviewing more MRI studies of patients with AIDS and by using statistical analysis they have concluded that though the frequency of lymphoma and toxoplasmosis is 30% and 52% respectively, a solitary lesion on MRI is more likely to be lymphoma than toxoplasmosis (56% vs 34%). Therefore, the authors have suggested that patients with solitary lesions on MRI undergo an early biopsy and initiation of appropriate treatment. Diana has shown that among patients with AIDS and confirmed CNS lymphoma, 50% had a lesion on the periventricular region and about 38% of them showed a subependymal spread or ventricular encasement. About 33% of the lesions in the plain CT scan were hyperdense. In contrast, only about 3% of the patients with AIDS and diagnosed toxoplasmosis had a lesion in the periventricular region and none of them showed any subependymal spread or ventricular encasement. Also, none of the lesions in the plain CT scan were hyperdense.
Despite the lower sensitivity of CT scan, it would be still appropriate and useful as a screening test for patients with suspected CNS toxoplasmosis, as only about 3% of cases will have normal scan at the time of presentation. MRI need only be used when the CT scan is negative for a lesion or when it reveals a solitary lesion.
Management : When a patient with HIV-1 infection presents with signs and symptoms referable to a focal intracranial involvement, the most useful investigation is diagnostic neuroimaging. Though MRI with contrast is the most sensitive study for picking up intracranial mass lesions, this is not easily available and affordable in our country. In spite of its known limitations CT scan with double dose contrast is sensitive enough to pick about 90-95% of mass lesions. If CT scan is normal or reveals only brain atrophy, diffuse white matter lesions, and non-enhancing lesions without mass effect typical of HIV encephalitis or PML, further CSF and serological tests should be carried out.
If intracranial mass lesion(s) is detected, then further management will depend on the clinical condition of the patient and the results of the imaging study. In patients with minimal evidence of raised intracranial pressure and definite evidence of multiple mass lesions on CT or MRI, an empirical therapy with anti-toxoplasmosis agents should be instituted., However, if there is only a single lesion seen on CT scan then a MRI is helpful in confirming the solitary nature of the lesion. Studies have shown that only about 14-34% of single lesions on MRI later prove to be toxoplasmosis., In case of a solitary lesion, the results of serological studies prove to be useful. If the studies are negative for toxoplasmosis, empirical therapy is not indicated. In such instances, stereotactic biopsy of the lesion is indicated for diagnosis and instituting appropriate treatment.
Surgical Therapy : If there is a large lesion with clinical signs of impending herniation, then surgery to achieve decompression of the lesion is required. However, if the patient harbors a large lesion and is clinically stuporous, an open surgery may be avoided and an immediate STB of the lesion done to confirm diagnosis. In this instance, empirical therapy for toxoplasmosis is not indicated, as there is serious risk of death in case of delay in instituting appropriate treatment.
Even though the likelihood of AIDS transmission to hospital workers is small, sufficient precautions need to be observed, when any surgical procedure is contemplated in these patients. It is recommended that the precautions appropriate for Hepatitis-B infected patients be applied to patients with AIDS or suspected AIDS. Some of the few precautions include wearing protective gown and masks, usage of gloves while handling blood samples or infected material, avoiding accidental injuries with needles and scalpel and the use of protective eye wear whenever aerosols is anticipated during the procedure. Appropriate sterilisation protocols and disposal of articles used during the procedure should be followed.
Medical Therapy : Treatment with a combination therapy with sulphadiazine and pyrimethamine, both of which cross the blood brain barrier, is the current recommended therapy for CNS toxoplasmosis. These drugs interfere with folic acid metabolism within the organism and therefore are only effective against the actively multiplying trophozoites and not against latent cysts. Pyrimethamine is administered in an initial oral loading dose of 200 mg followed by a dose of 50-75 mg per day, while sulfadiazine is administered in doses of 4-6 gm per day in 4 equal doses. Folinic acid needs to be given in doses as high as 50mg/day to offset the haematological toxicity, that usually follows therapy with these agents. Clindamycin in doses of 1200-1800 mg/day may be used as an alternative to sulphadiazine in instances where severe drug toxicity occurs with the latter. Side effects do occur in about 35-70% of the patients and may force withdrawal in about 40% of patients. The common side effects are skin rashes, leukopaenia and thrombocytopaenia. Toxicity is more common with sulphadiazine than with clindamycin. Since the combination therapy is useful only against actively dividing trophozoites, the disease is never eradicated. Therefore treatment is required to be continued indefinitely as the relapse rate after stopping medications is greater than 30%.16,21 Studies have shown that twice weekly, intermittent maintenance therapy with pyrimethamine and sulphadiazine may be as useful in preventing relapses as daily therapy with the above drugs.
Monitoring of Patients : Patients treated empirically against toxoplasmosis require to be monitored carefully for a period of 14-21 days for both clinical and radiological response to treatment. Porter et al have shown that 95% of the patients who show response to drug therapy, do so within 14 days. Failure to respond to treatment or worsening of symptoms require that the patient undergo a STB to confirm diagnosis. If there is response to treatment then it should be continued indefinitely with regular follow up.
HIV testing is recommended for all patients before elective neurosurgery and CNS toxoplasmosis should be suspected in every patient infected with HIV and presenting with CNS symptoms. Empirical therapy should be started in all the patients with multiple lesions on CT scan, except in instances where the lesion is solitary even on MRI and serological studies are negative. In these cases biopsy should be done, as also in patients who are stuporous, as they can ill afford to wait for the next 2-3 weeks for clinical and radiographic follow up. Decompression and excision of large lesions with midline shifts will have to be carried out. Adequate precaution should be taken at the time of performing any surgical procedure on these patients. Side effects frequently limit safe therapy with anti-toxoplasmosis agents.