1. TOXOPLASMOSIS Dr. S.GOPALAKRISHNAN. M.D Asst. Prof. Govt. Hospital for Thoracic Medicine Tambaram.

2. INTRODUCTION Toxoplasma Gondii is worldwide in distribution. Toxoplasma Gondii is worldwide in distribution. Most common Chronic infection with Obligate intracellular Protozoan in Humans. Most common Chronic infection with Obligate intracellular Protozoan in Humans. 3-4 % of all Patients with AIDS may develop CNS Toxoplasmosis at some stage. 3-4 % of all Patients with AIDS may develop CNS Toxoplasmosis at some stage. Greatest incidence when CD4 < 100 cells/mm 3 Greatest incidence when CD4 < 100 cells/mm 3 Decrease in CMI in chronically infected at risk of reactivation of infection. Decrease in CMI in chronically infected at risk of reactivation of infection.

3. EPIDEMIOLOGY Definite Host – CAT Definite Host – CAT Sexual Cycle----Oocyst Sexual Cycle----Oocyst Intermediate Host– Human,Mouse,Pig,Sheep. Intermediate Host– Human,Mouse,Pig,Sheep. Asexual Cycle----Tissue cyst Asexual Cycle----Tissue cyst

4. EPIDEMIOLOGY Transmission to humans Transmission to humans Oral Oral Ingestion of under cooked Pork or Lamb Ingestion of under cooked Pork or Lamb meat –tissue cyst. meat –tissue cyst. Exposure to oocysts Exposure to oocysts Ingestion of contaminated vegetables Ingestion of contaminated vegetables direct Contact with cat feces. direct Contact with cat feces. Others Others Transplacental. Transplacental. Blood Product Transfusion. Blood Product Transfusion. Organ Transplantation. Organ Transplantation.

5. PATHOGENESIS ORAL INGESTION TACHYZOITE (INVASIVE FORM) DISSEMINATES THROUGH OUT THE BODY INFECTION ->ANY NUCLEATED CELL->MULTIPLICATION -> CELL DESTRUCTION -> NECROTIC FOCI -> SURROUNDING INFLAMMATION TISSUE CYST LIFE LONG CHRONIC INFECTION ONSET OF CMI

6. SUSCEPTIBILITY – MECHANISM IN HIV Depletion of CD4 T cells Depletion of CD4 T cells Decreased production of IL-2,IL-12,IFN-  Decreased production of IL-2,IL-12,IFN-  Decreased cytotoxic T-lymphocyte activity. Decreased cytotoxic T-lymphocyte activity.

7. CLINICAL PRESENTATION Immuno compromised Cerebral Manifests primarily as toxoplasmic encephalitis Manifests primarily as toxoplasmic encephalitis Altered mental status – 75 % Altered mental status – 75 % Focal Neurological deficit – 70 % Focal Neurological deficit – 70 % Motor weakness Motor weakness Speech Disturbances Speech Disturbances Cranial Nerve Palsy Cranial Nerve Palsy Movement Disorders Movement Disorders Visual Field Defects Visual Field Defects Sensory,Cerebellar Dysfunction Sensory,Cerebellar Dysfunction

8. Head ache – 56% Head ache – 56% Fever – 45% Fever – 45% Seizures – 30% Seizures – 30% Extra Cereberal Ocular Ocular Choreoretinitis – Less common than CMV Choreoretinitis – Less common than CMV Lesions adjacent to disc, old scar Lesions adjacent to disc, old scar Multi focal, bilateral lesions typically more confluent, thick, opaque. Multi focal, bilateral lesions typically more confluent, thick, opaque. Anterior Uveitis Anterior Uveitis Cont…

9. Cont… Pulmonary Highly Lethal sepsis like syndrome Highly Lethal sepsis like syndrome Difficult to distinguish from Pneumocystis cari. pneumonia Difficult to distinguish from Pneumocystis cari. pneumonia Cardiac Cardiac Asymptomatic Asymptomatic Cardiac tamponade Cardiac tamponade Biventricular Failure Biventricular Failure

10. IMMUNOCOMPETENT LYMPHADENOPATHY LYMPHADENOPATHY Common – CERVICAL (Single or Multiple non tender,Discrete) Common – CERVICAL (Single or Multiple non tender,Discrete) Generalized – 20-30% Generalized – 20-30% Fever,Myalgia,Rash, Meningo-Encephalitis. Fever,Myalgia,Rash, Meningo-Encephalitis. Rare: Pneumonia,Myocarditis,Polymyositis. Rare: Pneumonia,Myocarditis,Polymyositis.

11. DIAGNOSIS * Serology * Serology Anti-IgG Antibodies Anti-IgG Antibodies Peaks within 1-2 months after infection. Peaks within 1-2 months after infection. Remain elevated for life. Remain elevated for life. False negative 10-15% False negative 10-15% Sabin-feldman dye test-gold standard Sabin-feldman dye test-gold standard IFA-indirect IFA-indirect Elisa Elisa

12. IgM Anti-body tests IgM Anti-body tests Double sandwich Elisa Double sandwich Elisa IFA IFA Immunosorbent agglutination assay Immunosorbent agglutination assay (IgM-ISAGA) (IgM-ISAGA) Cont…

13. SEROLOGY To diagnose – recent infection Serial specimens at 3 weeks apart-4 fold increase in IgG titre. Serial specimens at 3 weeks apart-4 fold increase in IgG titre.OR Elevated IgM, IgA or IgE titres with differential agglutination test. Elevated IgM, IgA or IgE titres with differential agglutination test. Useful to Identify - HIV at risk of developing toxoplasmosis. 97%-100% HIV with toxo – encephalitis have anti IgG anti bodies. Useful to Identify - HIV at risk of developing toxoplasmosis. 97%-100% HIV with toxo – encephalitis have anti IgG anti bodies.

14. CSF Non specific Non specific Mild cell count – mononuclear, protein Mild cell count – mononuclear, protein Intrathecal Anti IgG antibodies production Intrathecal Anti IgG antibodies production Ratio > 1 supports the diagnosis of toxoplsmic encephalitis Ratio > 1 supports the diagnosis of toxoplsmic encephalitis Wright – Giemsa stain of CSF Wright – Giemsa stain of CSF

15. DNA POLYMERASE CHAIN REACTION (PCR) POLYMERASE CHAIN REACTION (PCR) CSF – Sensitivity 50 – 60% CSF – Sensitivity 50 – 60% - Specificity 100% - Specificity 100% Bronchoalveolar lavage fluid Bronchoalveolar lavage fluid Vitreous and aqueous humor Vitreous and aqueous humor Blood samples – low sensitivity: toxo.encpha. Blood samples – low sensitivity: toxo.encpha. Amniotic fluid Amniotic fluid Culture – Time consuming Culture – Time consuming

16. NEURORADIOLOGIC STUDIES C T C T Multiple, bilateral, hypodense, contrast- enhancing focal brain lesions – 70 to 80% Multiple, bilateral, hypodense, contrast- enhancing focal brain lesions – 70 to 80% Lesions – basal ganglia, hemispheric corticomedullary junction. Lesions – basal ganglia, hemispheric corticomedullary junction. Contrast enhancement often with ringlike pattern Contrast enhancement often with ringlike pattern

17. MRI More sensitive than CT More sensitive than CT Identify more lesions than seen on CT, new lesions not seen on CT Identify more lesions than seen on CT, new lesions not seen on CT NEWER IMAGING TECHNIQUES 201T1 SPECT: Thallium 201 single- photon emission computed tomography 18F FDG – PET: Fluoride 18 - Flouro – 2 deoxyglucose positron emission tomography.

18. Toxoplasmosis

19. Toxoplasmosis- Response to therapy

20. Toxoplasmosis

21. DEFINITE DIAGNOSIS Excisional Brain Biopsy: Excisional Brain Biopsy: Usually not performed Usually not performed Reserved for patients who fail to respond to therapy Reserved for patients who fail to respond to therapy

22. DIFFERENTIAL DIAGNOSIS Primary CNS Lymphoma Primary CNS Lymphoma Mycobacterial infections Mycobacterial infections Cryptococcal meningitis Cryptococcal meningitis Herpes simplex encephalitis Herpes simplex encephalitis PML PML CMV infection CMV infection Infectious mononucleosis Infectious mononucleosis

23. MANAGEMENT IN HIV Therapy empiric in most cases Therapy empiric in most cases Neurologic response Neurologic response 51% by day 3 51% by day 3 91% by day 14 91% by day 14 Neuroradiologic study repeated 2-4 weeks after initiation of therapy Neuroradiologic study repeated 2-4 weeks after initiation of therapy

24. Cont… Acute Therapy Acute Therapy Maintenance Therapy Maintenance Therapy (Secondary Prophylaxis) (Secondary Prophylaxis) Prevention (Primary Prophylaxis) Prevention (Primary Prophylaxis) Discontinuation of Prophylaxis Discontinuation of Prophylaxis

25. ACUTE THERAPY Preferred Preferred Pyrimethamine 200mg po loading dose followed by 75-100 mg po qd plus folinic acid 15-20 mg po qd plus sulfadiazine 1-1.5g po q6h - 6 weeks. Pyrimethamine 200mg po loading dose followed by 75-100 mg po qd plus folinic acid 15-20 mg po qd plus sulfadiazine 1-1.5g po q6h - 6 weeks. Alternatives Alternatives Pyrimethamine with folinic acid (as standard) with one of the following: Pyrimethamine with folinic acid (as standard) with one of the following: Clindamycin 600 mg po q6h Clindamycin 600 mg po q6h Clarithromycin 1g po bid Clarithromycin 1g po bid Azithromycin 1.2-1.5g po qd Azithromycin 1.2-1.5g po qd Dapsone 100mg po qd - 6 weeks Dapsone 100mg po qd - 6 weeks

26. MAINTENANCE THERAPY Preferred Preferred Pyrimethamine 25 mg po qd & folinic acid 10 mg po qd and Sulfadiazine 500-1000 mg po Pyrimethamine 25 mg po qd & folinic acid 10 mg po qd and Sulfadiazine 500-1000 mg po q 6h q 6h Alternative Alternative Pyrimethamine 25 mg po qd & folinic acid 5- 10 mg qd po & Clindamycin 300-450 mg po q6-8h. Pyrimethamine 25 mg po qd & folinic acid 5- 10 mg qd po & Clindamycin 300-450 mg po q6-8h. Atovaquone 750 mg po bid Atovaquone 750 mg po bid

27. PREVENTION To eat well cooked meat - internal temperature of 116 0 C, or no longer pink inside. To eat well cooked meat - internal temperature of 116 0 C, or no longer pink inside. Proper hand washing. Proper hand washing. Fruits and vegetables should be washed prior to consumption. Fruits and vegetables should be washed prior to consumption. To avoid contact with materials contaminated with cat feces, handling cat litter boxes. To avoid contact with materials contaminated with cat feces, handling cat litter boxes. To wear gloves during gardening. To wear gloves during gardening.

28. Cont… Recommended Recommended T gondii - Seropositive patients with CD4 T cell counts <100 regardless of clinical status. T gondii - Seropositive patients with CD4 T cell counts <100 regardless of clinical status. Patients with CD4 T cell counts <200 if an opportunistic infection or malignancy develops. Patients with CD4 T cell counts <200 if an opportunistic infection or malignancy develops. Trimethorprim / sulfamethazole 1 ds tab po qd Trimethorprim / sulfamethazole 1 ds tab po qd Dapsone 50 m po qd & pyrimethamine 50 mg po q week plus & folinic acid 25 mg po q week Dapsone 50 m po qd & pyrimethamine 50 mg po q week plus & folinic acid 25 mg po q week

29. DISCONTINUATION OF PROPHYLAXIS CD4 T cell counts increase to more than 200 over a period of 3- 6 months in response to HAART CD4 T cell counts increase to more than 200 over a period of 3- 6 months in response to HAART Restarting prophylaxis in patients CD4 T cell counts decrease to < 200 Restarting prophylaxis in patients CD4 T cell counts decrease to < 200